Compositions and methods for controlling nematodes

ABSTRACT

Compositions and processes for controlling nematodes are described herein, e.g., nematodes that infest plants or animals. The compounds include oxazoles, oxadiazoles and thiadiazoles.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of pending U.S. patent application Ser.No. 12/190,989, filed Aug. 13, 2008, and claims the benefit of U.S.Provisional Patent Application Ser. No. 60/955,448, filed Aug. 13, 2007,the entire disclosures of which are herein incorporated by reference.

BACKGROUND OF THE INVENTION

Nematodes (derived from the Greek word for thread) are active, flexible,elongate, organisms that live on moist surfaces or in liquidenvironments, including films of water within soil and moist tissueswithin other organisms. While only 20,000 species of nematode have beenidentified, it is estimated that 40,000 to 10 million actually exist.Many species of nematodes have evolved to be very successful parasitesof plants and animals and are responsible for significant economiclosses in agriculture and livestock and for morbidity and mortality inhumans (Whitehead (1998) Plant Nematode Control. CAB International, NewYork).

Nematode parasites of plants can infest all parts of plants, includingroots, developing flower buds, leaves, and stems. Plant parasites areclassified on the basis of their feeding habits into the broadcategories migratory ectoparasites, migratory endoparasites, andsedentary endoparasites. Sedentary endoparasites, which include the rootknot nematodes (Meloidogyne) and cyst nematodes (Globodera andHeterodera) induce feeding sites and establish long-term infectionswithin roots that are often very damaging to crops (Whitehead, supra).It is estimated that parasitic nematodes cost the horticulture andagriculture industries in excess of $78 billion worldwide a year, basedon an estimated average 12% annual loss spread across all major crops.For example, it is estimated that nematodes cause soybean losses ofapproximately $3.2 billion annually worldwide (Barker et al. (1994)Plant and Soil Nematodes: Societal Impact and Focus for the Future. TheCommittee on National Needs and Priorities in Nematology. CooperativeState Research Service, US Department of Agriculture and Society ofNematologists). Several factors make the need for safe and effectivenematode controls urgent. Continuing population growth, famines, andenvironmental degradation have heightened concern for the sustainabilityof agriculture, and new government regulations may prevent or severelyrestrict the use of many available agricultural anthelmintic agents.

There are a very small array of chemicals available to effectivelycontrol nematodes (Becker (1999) Agricultural Research Magazine47(3):22-24; U.S. Pat. No. 6,048,714). In general, chemical nematicidesare highly toxic compounds known to cause substantial environmentaldamage and are increasingly restricted in the amounts and locations inwhich they can be used. For example, the soil fumigant methyl bromidewhich has been used effectively to reduce nematode infestations in avariety of specialty crops, is regulated under the U.N. MontrealProtocol as an ozone-depleting substance and is undergoing phase out inthe US and worldwide (Carter (2001) California Agriculture, 55(3):2). Itis expected that strawberry and other commodity crop industries will besignificantly impacted if a suitable replacement for methyl bromide isnot found. Similarly, broad-spectrum nematicides such as Telone (variousformulations of 1,3-dichloropropene) have significant restrictions ontheir use because of toxicological concerns (Carter (2001) CaliforniaAgriculture, 55(3):12-18). Organophosphate and carbamate pesticides areanother important class of nematicides undergoing regulatory review andseveral of these compounds are currently being phase out (e.g.,fenamiphos, terbufos, cadusafos).

To date little success has been achieved in finding safe effectivereplacements for the toxic but efficacious conventional nematicides. Arecent example of the poor efficacy of many newer potential replacementsfor organophosphates and carbamates is the study of alternatives tofenamiphos for management of plant parasitic nematodes in bermudagrass.In these trials, none of the experimental treatments reduced populationdensities of the plant parasitic nematodes, or consistently promotedturf visual performance or turf root production (Crow (2005) Journal ofNematology, 37(4):477-482). Consequently there remains an urgent need todevelop environmentally safe, efficacious methods of controlling plantparasitic nematodes

Some plant species are known to be highly resistant to nematodes. Thebest documented of these include marigolds (Tagetes spp.), rattlebox(Crotalaria spectabilis), chrysanthemums (Chrysanthemum spp.), castorbean (Ricinus communis), margosa (Azardiracta indica), and many membersof the family Asteraceae (family Compositae) (Hackney & Dickerson.(1975) J Nematol 7(1):84-90). In the case of the Asteraceae, thephotodynamic compound alpha-terthienyl has been shown to account for thestrong nematicidal activity of the roots. Castor beans are plowed underas a green manure before a seed crop is set. However, a significantdrawback of the castor plant is that the seed contains toxic compounds(such as ricin) that can kill humans, pets, and livestock and is alsohighly allergenic. In most cases however, the active principle(s) forplant nematicidal activity has not been discovered and it remainsdifficult to derive commercially successful nematicidal products fromthese resistant plants or to transfer the resistance to crops ofagronomical importance such as soybeans and cotton.

Genetic resistance to certain nematodes is available in some commercialcultivars (e.g., soybeans), but these are restricted in number and theavailability of cultivars with both desirable agronomic features andresistance is limited. Furthermore, the production of nematode resistantcommercial varieties by conventional plant breeding based on geneticrecombination through sexual crosses is a slow process and is oftenfurther hampered by a lack of appropriate germplasm.

Chemical means of controlling plant parasitic nematodes continue to beessential for many crops which lack adequate natural resistance or asource of transgenic resistance. In the specialty markets, economichardship resulting from nematode infestation is particularly high instrawberries, bananas, and other high value vegetables and fruits. Inthe high-acreage crop markets, nematode damage is greatest in soybeansand cotton. There are however, dozens of additional crops that sufferfrom significant nematode infestation including potato, pepper, onion,citrus, coffee, sugarcane, greenhouse ornamentals and golf course turfgrasses.

To be useful in modern agriculture nematicides must have high potency, abroad spectrum of activity against different strains of nematodes andshould not be toxic to non-target organisms.

Nematode parasites of vertebrates (e.g., humans, livestock and companionanimals) include gut roundworms, hookworms, pinworms, whipworms, andfilarial worms. They can be transmitted in a variety of ways, includingby water contamination, skin penetration, biting insects, or byingestion of contaminated food.

In domesticated animals, nematode control or “de-worming” is essentialto the economic viability of livestock producers and is a necessary partof veterinary care of companion animals. Parasitic nematodes causemortality in animals (e.g., heartworm in dogs and cats) and morbidity asa result of the parasites' inhibiting the ability of the infected animalto absorb nutrients. The parasite-induced nutrient deficiency leads todisease and stunted growth in livestock and companion animals. Forinstance, in cattle and dairy herds, a single untreated infection withthe brown stomach worm can permanently restrict an animal's ability toconvert feed into muscle mass or milk.

Two factors contribute to the need for novel anthelmintics and vaccinesto control animal parasitic nematodes. First, some of the more prevalentspecies of parasitic nematodes of livestock are building resistance tothe anthelmintic drugs available currently, meaning that these productsare losing their efficacy. These developments are not surprising becausefew effective anthelmintic drugs are available and most have been usedcontinuously. Some parasitic species have developed resistance to mostof the anthelmintics (Geents et al. (1997) Parasitology Today13:149-151; Prichard (1994) Veterinary Parasitology 54:259-268). Thefact that many of the anthelmintic drugs have similar modes of actioncomplicates matters, as the loss of sensitivity of the parasite to onedrug is often accompanied by side resistance—that is, resistance toother drugs in the same class (Sangster & Gill (1999) Parasitology Today15(4):141-146). Secondly, there are some issues with toxicity for themajor compounds currently available.

Infections by parasitic nematode worms also result in substantial humanmortality and morbidity, especially in tropical regions of Africa, Asia,and the Americas. The World Health Organization estimates 2.9 billionpeople are infected, and in some areas, 85% of the population carriesworms. While mortality is rare in proportion to infections, morbidity issubstantial and rivals diabetes and lung cancer in worldwide disabilityadjusted life year (DALY) measurements.

Examples of human parasitic nematodes include hookworms, filarial worms,and pinworms. Hookworms (1.3 billion infections) are the major cause ofanemia in millions of children, resulting in growth retardation andimpaired cognitive development. Filarial worms invade the lymphatics,resulting in permanently swollen and deformed limbs (elephantiasis), andthe eyes, causing African river blindness. The large gut roundwormAscaris lumbricoides infects more than one billion people worldwide andcauses malnutrition and obstructive bowel disease. In developedcountries, pinworms are common and often transmitted through children indaycare.

Even in asymptomatic parasitic infections, nematodes can still deprivethe host of valuable nutrients and increase the ability of otherorganisms to establish secondary infections. In some cases, infectionscan cause debilitating illnesses and can result in anemia, diarrhea,dehydration, loss of appetite, or death.

Despite some advances in drug availability and public healthinfrastructure and the near elimination of one tropical nematode (thewater-borne Guinea worm), most nematode diseases have remainedintractable problems. Treatment of hookworm diseases with anthelminticdrugs, for instance, has not provided adequate control in regions ofhigh incidence because rapid re-infection occurs after treatment. Infact, over the last 50 years, while nematode infection rates have fallenin the United States, Europe, and Japan, the overall number ofinfections worldwide has kept pace with the growing world population.Large scale initiatives by regional governments, the World HealthOrganization, foundations, and pharmaceutical companies are now underwayattempting to control nematode infections with currently availabletools, including three programs for control of Onchocerciasis (riverblindness) in Africa and the Americas using ivermectin and vectorcontrol; The Global Alliance to Eliminate Lymphatic Filariasis usingDEC, albendazole, and ivermectin; and the highly successful Guinea WormEradication Program. Until safe and effective vaccines are discovered toprevent parasitic nematode infections, anthelmintic drugs will continueto be used to control and treat nematode parasitic infections in bothhumans and domestic animals.

Certain insecticidal oxazoles (U.S. Pat. No. 4,791,124) and thiazoles(U.S. Pat. No. 4,908,357) and nematicidal pyrazoles (U.S. Pat. No.6,310,049) have been disclosed in the art. The present inventiondiscloses other oxazoles, oxadiazoles and thiadiazoles with surprisinglypotent nematicidal activity showing activity comparable to commercialstandards. Commercial level nematicidal potency has not previously beendemonstrated with oxazoles, oxadiazoles and thiadiazoles. Importantly,these compounds are broadly active against nematodes yet safe tonon-target organisms.

U.S. Pat. No. 4,791,124 disclosed certain oxazoles and thiazoles withnematicidal activity against Meloidogyne incognita (root knot nematode)at 10 parts per million. However, compounds were not titrated to lowerdoses, and as can be seen in table 1D herein certain thiazole analogswhich appear highly efficacious at 8 ppm are not comparable in potencyto commercial standards and as they do not retain appreciablenematicidal activity at 1 ppm.

U.S. Pat. No. 6,310,049 discloses certain nematicidal pyrazoles withactivity against root knot nematode. Several pyrazole compounds areshown having activity at 100 ppm in an in vitro assay with a smallsubset of the compounds having activity at 50 ppm in a soil basedgreenhouse. One compound is disclosed as having greenhouse activity at20 ppm and a single compound as having greenhouse activity at 5 ppm. Itis not clear if any of these compounds have potency comparable tocommercial standards, i.e., at 1 ppm. As can be seen in table 1D herein,nematicidal activity is seen for 3-(furan-2-yl)-5-phenyl-1H-pyrazole at8 ppm but not 1 ppm whereas many oxazoles and oxadiazoles havenematicidal potency comparable to commercial standards at 1 ppm.

Some oxadiazoles compounds having substituted furan or thiophene ringsbut not unsubstituted furan or thiophene rings are disclosed as beingapoptosis inducers and useful as chemotherapeutic against certaincancers (Zhang et al. 2005 J Med Chem. 48(16):5215-23). Notwithstandingsome superficial chemical similarities the nematicidal analogs of thisinvention do not induce apoptosis in mammalian cells and have equalpotency against wild type C. elegans nematodes and ced-3 or ced-4 C.elegans mutants deficient in apoptosis. These analogs are thereforestructurally and functionally distinct from the apoptosis inducingoxadiazoles disclosed by Cai et al in U.S. Pat. No. 7,041,685.

SUMMARY OF THE INVENTION

Compositions and processes for controlling nematodes are describedherein, e.g., nematodes that infest plants or the situs of plants.Nematodes that parasitize animals can also be controlled using themethods and compounds described herein.

Described herein are nematicidal compositions comprising an effectiveamount of a compound or a mixture of compounds having any of the formuladescribed herein, for example the compounds shown below.

Described herein are a compound of Formula I or a salt thereof,

wherein,

A is phenyl, pyridyl, or pyrazyl each of which can be optionallyindependently substituted one or more substituents selected from:halogen, CF₃, CH₃, OCF₃, OCH₃, CN and C(H)O;

B is C(H) or C(CH₃); and

C is thienyl, furanyl, oxazolyl or isoxazolyl each of which can beoptionally independently substituted with one or more substituentsselected from: fluorine, chlorine, CH₃, and OCF₃.

In various embodiments: A is phenyl; A is pyridyl; A is pyrazyl; B isC(H); B is C(CH₃); C is thienyl; C is furanyl; C is oxazolyl; and C isisoxazolyl.

Also disclosed are compounds having Formula Ia or a salt thereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃,and OCF₃,

with the proviso that R₁ and R₅ cannot be simultaneously hydrogen;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₇ and R₈ are independently selected from hydrogen and fluorine;

R₉ is selected from hydrogen, F, Cl, CH₃, and OCF₃;

B is C(H) or C(CH₃); and

E is 0 or S.

In various embodiments of the compound of Formula Ia: R₁ and R₅ areindependently selected from hydrogen, fluorine and chlorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen; R₁ and R₅ areindependently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, and R₃ isselected from Cl, Br and F; R₁ and R₅ are independently selected fromhydrogen, chlorine and fluorine with the proviso that R₁ and R₅ cannotbe simultaneously hydrogen and R₃ is selected from Cl and Br; R₁ and R₅are independently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, R₃ is selectedfrom Cl, Br, F, and E is S; R₁ and R₅ are independently selected fromhydrogen, chlorine and fluorine with the proviso that R₁ and R₅ cannotbe simultaneously hydrogen, R₃ is selected from Cl, Br, and F, E is S,and both R₂ and R₄ are hydrogen; R₁ and R₅ are independently selectedfrom hydrogen, chlorine and fluorine with the proviso that R₁ and R₅cannot be simultaneously hydrogen, R₃ is selected from Cl, Br, F, E isS, both R₂ and R₄ are hydrogen and R₇, R₈ and R₉ are all hydrogen orfluorine; R₁ and R₅ are independently selected from hydrogen, chlorineand fluorine with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ selected from Cl, E is S, both R₂ and R₄ are hydrogen, andR₇, R₈ and R₉ are all hydrogen or fluorine; and R₁ and R₅ areindependently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, R₃ is selectedfrom Br, E is S, both R₂ and R₄ are hydrogen and R₇, R₈ and R₉ are allhydrogen or fluorine; R₁ and R₅ are independently selected from hydrogenand fluorine with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ is selected from Cl, E is S, R₂ and R₄ both are hydrogenand R₇, R₈ and R₉ are hydrogen; R₁ and R₅ are independently selectedfrom hydrogen, chlorine and fluorine with the proviso that R₁ and R₅cannot be simultaneously hydrogen, R₃ is s Br, E is S, both R₂ and R₄are hydrogen, and R₇, R₈ and R₉ are all hydrogen.

Also disclosed are compounds having Formula Ib or a salt thereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃,and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andCO;

R₈ is selected from hydrogen and fluorine;

R₆ and R₉ are independently selected from hydrogen, F, Cl, CH₃, andOCF₃;

B is C(H) or C(CH₃); and

E is 0 or S.

In various embodiments of the compound of Formula Ib: R₁ and R₅ areindependently selected from hydrogen, fluorine and chlorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen; R₁ and R₅ areindependently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, and R₃ isselected from Cl, Br and F; R₁ and R₅ are independently selected fromhydrogen, chlorine and fluorine with the proviso that R₁ and R₅ cannotbe simultaneously hydrogen and R₃ is selected from Cl and Br; R₁ and R₅are independently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, R₃ is selectedfrom Cl, Br, F, and E is S; R₁ and R₅ are independently selected fromhydrogen, chlorine and fluorine with the proviso that R₁ and R₅ cannotbe simultaneously hydrogen, R₃ is selected from Cl, Br, and F, E is S,and both R₂ and R₄ are hydrogen; R₁ and R₅ are independently selectedfrom hydrogen, chlorine and fluorine with the proviso that R₁ and R₅cannot be simultaneously hydrogen, R₃ is selected from Cl, Br, F, E isS, both R₂ and R₄ are hydrogen and R₇, R₈ and R₉ are all hydrogen orfluorine; R₁ and R₅ are independently selected from hydrogen, chlorineand fluorine with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ selected from Cl, E is S, both R₂ and R₄ are hydrogen, andR₇, R₈ and R₉ are all hydrogen or fluorine; and R₁ and R₅ areindependently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, R₃ is selectedfrom Br, E is S, both R₂ and R₄ are hydrogen and R₇, R₈ and R₉ are allhydrogen or fluorine; R₁ and R₅ are independently selected from hydrogenand fluorine with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ is selected from Cl, E is S, R₂ and R₄ both are hydrogenand R₇, R₈ and R₉ are hydrogen; R₁ and R₅ are independently selectedfrom hydrogen, chlorine and fluorine with the proviso that R₁ and R₅cannot be simultaneously hydrogen, R₃ is s Br, E is S, both R₂ and R₄are hydrogen, and R₇, R₈ and R₉ are all hydrogen.

Disclosed herein are compounds of Formula II or a salt thereof,

wherein,

A is selected from: phenyl, pyridyl, and pyrazyl, each of which can beoptionally independently substituted with one or more substituentsselected from: halogen, CF₃, CH₃, OCF₃, OCH₃, CN, and C(H)O;

B is C(H) or C(CH₃);

C is selected from: thienyl, furanyl, oxazolyl or isoxazolyl, each ofwhich can be optionally independently substituted with one or moresubstituents selected from: fluorine, chlorine, CH₃, and OCF₃.

In various embodiments: A is phenyl; A is pyridyl; A is pyrazyl; B isC(H); B is C(CH₃); C is thienyl; C is furanyl; C is oxazolyl; and C isisoxazolyl.

Disclosed herein are compounds having Formula IIa

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃and OCF₃

with the proviso that R₁ and R₅ cannot be simultaneously hydrogen;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₇ and R₈ are independently selected from hydrogen and F;

R₉ is selected from hydrogen, F, Cl, CH₃, and OCF₃;

B is C(H) or C(CH₃); and

E is O or S.

In various embodiments of the compound of Formula IIa: R₁ and R₅ areindependently selected from hydrogen, fluorine and chlorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen; R₁ and R₅ areindependently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, and R₃ isselected from Cl, Br and F; R₁ and R₅ are independently selected fromhydrogen, chlorine and fluorine with the proviso that R₁ and R₅ cannotbe simultaneously hydrogen and R₃ is selected from Cl and Br; R₁ and R₅are independently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, R₃ is selectedfrom Cl, Br, F, and E is S; R₁ and R₅ are independently selected fromhydrogen, chlorine and fluorine with the proviso that R₁ and R₅ cannotbe simultaneously hydrogen, R₃ is selected from Cl, Br, and F, E is S,and both R₂ and R₄ are hydrogen; R₁ and R₅ are independently selectedfrom hydrogen, chlorine and fluorine with the proviso that R₁ and R₅cannot be simultaneously hydrogen, R₃ is selected from Cl, Br, F, E isS, both R₂ and R₄ are hydrogen and R₇, R₈ and R₉ are all hydrogen orfluorine; R₁ and R₅ are independently selected from hydrogen, chlorineand fluorine with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ selected from Cl, E is S, both R₂ and R₄ are hydrogen, andR₇, R₈ and R₉ are all hydrogen or fluorine; and R₁ and R₅ areindependently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, R₃ is selectedfrom Br, E is S, both R₂ and R₄ are hydrogen and R₇, R₈ and R₉ are allhydrogen or fluorine; R₁ and R₅ are independently selected from hydrogenand fluorine with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ is selected from Cl, E is S, R₂ and R₄ both are hydrogenand R₇, R₈ and R₉ are hydrogen; R₁ and R₅ are independently selectedfrom hydrogen, chlorine and fluorine with the proviso that R₁ and R₅cannot be simultaneously hydrogen, R₃ is s Br, E is S, both R₂ and R₄are hydrogen, and R₇, R₈ and R₉ are all hydrogen.

Disclosed herein are compounds having Formula IIb or a salt thereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN andC(H)O;

R₈ is selected from hydrogen and fluorine;

R₆ and R₉ are independently selected from hydrogen, F, Cl, CH₃ and OCF₃;

B is C(H) or C(CH₃); and

E is O or S.

In various embodiments of the compound of Formula IIb: R₁ and R₅ areindependently selected from hydrogen, fluorine and chlorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen; R₁ and R₅ areindependently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, and R₃ isselected from Cl, Br and F; R₁ and R₅ are independently selected fromhydrogen, chlorine and fluorine with the proviso that R₁ and R₅ cannotbe simultaneously hydrogen and R₃ is selected from Cl and Br; R₁ and R₅are independently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, R₃ is selectedfrom Cl, Br, F, and E is S; R₁ and R₅ are independently selected fromhydrogen, chlorine and fluorine with the proviso that R₁ and R₅ cannotbe simultaneously hydrogen, R₃ is selected from Cl, Br, and F, E is S,and both R₂ and R₄ are hydrogen; R₁ and R₅ are independently selectedfrom hydrogen, chlorine and fluorine with the proviso that R₁ and R₅cannot be simultaneously hydrogen, R₃ is selected from Cl, Br, F, E isS, both R₂ and R₄ are hydrogen and R₇, R₈ and R₉ are all hydrogen orfluorine; R₁ and R₅ are independently selected from hydrogen, chlorineand fluorine with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ selected from Cl, E is S, both R₂ and R₄ are hydrogen, andR₇, R₈ and R₉ are all hydrogen or fluorine; and R₁ and R₅ areindependently selected from hydrogen, chlorine and fluorine with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, R₃ is selectedfrom Br, E is S, both R₂ and R₄ are hydrogen and R₇, R₈ and R₉ are allhydrogen or fluorine; R₁ and R₅ are independently selected from hydrogenand fluorine with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ is selected from Cl, E is S, R₂ and R₄ both are hydrogenand R₇, R₈ and R₉ are hydrogen; R₁ and R₅ are independently selectedfrom hydrogen, chlorine and fluorine with the proviso that R₁ and R₅cannot be simultaneously hydrogen, R₃ is s Br, E is S, both R₂ and R₄are hydrogen, and R₇, R₈ and R₉ are all hydrogen.

Disclosed herein are compounds of Formula III or a salt thereof,

wherein,

A is phenyl, pyridyl, or pyrazyl, each of which can be optionallyindependently substituted with one or more substituents selected from:halogen, CF₃, CH₃, OCF₃, OCH₃, CN and C(H)O.

C is thienyl, furanyl, oxazolyl or isoxazolyl each of which can beoptionally independently substituted with one or more substituentsselected from: fluorine, chlorine, CH₃ and OCF₃.

In various embodiments: A is phenyl; A is pyridyl; A is pyrazyl; C isthienyl; C is furanyl; C is oxazolyl; and C is isoxazolyl.

Also disclosed are compounds having Formula IIIa or a salt thereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃,and OCF₃,

with the proviso that R₁ and R₅ cannot be simultaneously hydrogen;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₇ and R₈ are independently selected from hydrogen and fluorine;

R₉ is selected from hydrogen, F, Cl, CH₃, and OCF₃; and

E is O or S.

In various embodiments of the compound of Formula IIIa: R₁ and R₅ areindependently selected from hydrogen and CH₃ with the proviso that R₁and R₅ cannot be simultaneously hydrogen, R₃ fluorine, chlorine orbromine, and E is O; R₁ and R₅ are independently selected from hydrogenand CH₃ with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ fluorine, chlorine and bromine, E is S, and R₉ is hydrogenor fluorine; R₁ and R₅ are independently selected from hydrogen and CH₃with the proviso that R₁ and R₅ cannot be simultaneously hydrogen, bothR₂ and R₄ are hydrogen, R₃ is chlorine or bromine, and E is O; R₁ and R₅are independently selected from hydrogen and CH₃ with the proviso thatR₁ and R₅ cannot be simultaneously hydrogen, both R₂ and R₄ arehydrogen, R₃ is chlorine or bromine, E is S, and R₉ is hydrogen orfluorine; R₁ and R₅ are independently selected from hydrogen and Cl, R₃is fluorine, chlorine or bromine, E is O, and R₉ is fluorine; R₁ and R₅are independently selected from hydrogen and CH₃ with the proviso thatR₁ and R₅ cannot be simultaneously hydrogen, R₃ is fluorine, chlorine orbromine, and E is O; R₁ and R₅ are independently selected from hydrogenand CH₃ with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ fluorine, chlorine or bromine, E is S, and R₉ is hydrogenor fluorine; R₁ and R₅ are independently selected from hydrogen and CH₃with the proviso that R₁ and R₅ cannot be simultaneously hydrogen, bothR₂ and R₄ are hydrogen, R₃ is chlorine or bromine, and E is O; R₁ and R₅are independently selected from hydrogen and CH₃ with the proviso thatR₁ and R₅ cannot be simultaneously hydrogen, R₂ and R₄ are hydrogen, R₃chlorine or bromine, E is S and R₉ is hydrogen or fluorine; R₁ and R₅are independently selected from hydrogen and CH₃ with the proviso thatR₁ and R₅ cannot be simultaneously hydrogen, both R₂ and R₄ arehydrogen, R₃ is chlorine or bromine, and E is O and R₇, R₈ and R₉ arehydrogen; and R₁ and R₅ are independently selected from hydrogen and Cl,R₃ fluorine, chlorine and bromine, E is O and R₉ is fluorine.

Also disclosed are compounds having Formula IIIb or a salt thereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃,and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₈ is selected from hydrogen and fluorine;

R₆ and R₉ are independently selected from hydrogen, F, Cl, CH₃, andOCF₃; and

E is O or S.

In various embodiments of the compound of Formula IIIb: R₁ and R₅ areindependently selected from hydrogen and CH₃ with the proviso that R₁and R₅ cannot be simultaneously hydrogen, R₃ fluorine, chlorine orbromine, and E is O; R₁ and R₅ are independently selected from hydrogenand CH₃ with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ fluorine, chlorine and bromine, E is S, and R₉ is hydrogenor fluorine; R₁ and R₅ are independently selected from hydrogen and CH₃with the proviso that R₁ and R₅ cannot be simultaneously hydrogen, bothR₂ and R₄ are hydrogen, R₃ is chlorine or bromine, and E is O; R₁ and R₅are independently selected from hydrogen and CH₃ with the proviso thatR₁ and R₅ cannot be simultaneously hydrogen, both R₂ and R₄ arehydrogen, R₃ is chlorine or bromine, E is S, and R₉ is hydrogen orfluorine; R₁ and R₅ are independently selected from hydrogen and Cl, R₃is fluorine, chlorine or bromine, E is O, and R₉ is fluorine; R₁ and R₅are independently selected from hydrogen and CH₃ with the proviso thatR₁ and R₅ cannot be simultaneously hydrogen, R₃ is fluorine, chlorine orbromine, and E is O; R₁ and R₅ are independently selected from hydrogenand CH₃ with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ fluorine, chlorine or bromine, E is S, and R₉ is hydrogenor fluorine; R₁ and R₅ are independently selected from hydrogen and CH₃with the proviso that R₁ and R₅ cannot be simultaneously hydrogen, bothR₂ and R₄ are hydrogen, R₃ is chlorine or bromine, and E is O; R₁ and R₅are independently selected from hydrogen and CH₃ with the proviso thatR₁ and R₅ cannot be simultaneously hydrogen, R₂ and R₄ are hydrogen, R₃chlorine or bromine, E is S and R₉ is hydrogen or fluorine; and R₁ andR₅ are independently selected from hydrogen and Cl, R₃ is fluorine,chlorine or bromine, E is O and R₉ is fluorine.

Also disclosed are compounds of Formula (IV) or a salt thereof

wherein,

A¹ is phenyl, pyridyl, pyrazyl, oxazolyl or isoxazolyl each of which canbe optionally independently substituted with one or more substituentsselected from: halogen, CF₃, CH₃, OCF₃, OCH₃, CN, and C(H)O; and

C¹ is thienyl, furanyl, oxazolyl or isoxazolyl, each of which can beoptionally independently substituted with one or more substituentsselected from fluorine, chlorine, CH₃, and OCF₃.

In various embodiments: A¹ is phenyl; A¹ is pyridyl; A¹ is pyrazyl; A¹is oxazolyl; A¹ is isoxazolyl; C¹ is thienyl; C¹ is furanyl; C¹ isoxazolyl; and C¹ is isoxazolyl.

Also disclosed are compounds having Formula IVa or a salt thereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃and OCF₃,

with the proviso that R₁ and R₅ cannot be simultaneously hydrogen;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₇ and R₈ are independently selected from hydrogen and fluorine;

R₉ is selected from hydrogen, F, Cl, CH₃, and OCF₃; and

E is O or S.

In various embodiments of the compound of Formula IVa: R₁ and R₅ areindependently selected from hydrogen and CH₃ with the proviso that R₁and R₅ cannot be simultaneously hydrogen, R₃ is fluorine, chlorine orbromine, and E is O; R₁ and R₅ are independently selected from hydrogenand CH3 with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, both R₂ and R₄ are hydrogen, R₃ is chlorine or bromine, and Eis O and R₇, R₈ and R₉ are hydrogen; R₁ and R₅ are independentlyselected from hydrogen and CH₃ with the proviso that R₁ and R₅ cannot besimultaneously hydrogen, R₃ is fluorine, chlorine or bromine, E is S,and R₉ is hydrogen or fluorine; R₁ and R₅ are independently selectedfrom hydrogen and CH₃ with the proviso that R₁ and R₅ cannot besimultaneously hydrogen, both R₂ and R₄ are hydrogen, R₃ is chlorine orbromine, E is O; R₁ and R₅ are independently selected from hydrogen andCH₃ with the proviso that R₁ and R₅ cannot be simultaneously hydrogen,both R₂ and R₄ are hydrogen, R₃ is chlorine or bromine, E is S, and R₉is hydrogen or fluorine; R₁ and R₅ are independently selected fromhydrogen and Cl, R₃ is fluorine, chlorine or bromine, E is O, and R₉ isfluorine.

Also disclosed are compounds having Formula IVb or a salt thereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃and OCF₃,

with the proviso that R₁ and R₅ cannot be simultaneously hydrogen;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₈ is selected from hydrogen and fluorine;

R₆ and R₉ are independently selected from hydrogen, F, Cl, CH₃, andOCF₃; and

E is O or S.

In various embodiments of the compound of Formula IVb: R₁ and R₅ areindependently selected from hydrogen and CH₃ with the proviso that R₁and R₅ cannot be simultaneously hydrogen, R₃ is fluorine, chlorine orbromine, and E is O; R₁ and R₅ are independently selected from hydrogenand CH₃ with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ is fluorine, chlorine or bromine, E is S, and R₉ ishydrogen or fluorine; R₁ and R₅ are independently selected from hydrogenand CH₃ with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, both R₂ and R₄ are hydrogen, R₃ is chlorine or bromine, E isO; R₁ and R₅ are independently selected from hydrogen and CH₃ with theproviso that R₁ and R₅ cannot be simultaneously hydrogen, both R₂ and R₄are hydrogen, R₃ is chlorine or bromine, E is S, and R₉ is hydrogen orfluorine; and R₁ and R₅ are independently selected from hydrogen and Cl,R₃ is fluorine, chlorine or bromine, E is O, and R₉ is fluorine.

Disclosed herein are compounds of Formula (V) or a salt thereof

wherein,

A¹ is phenyl, pyridyl, pyrazyl, oxazolyl or isoxazolyl, each of whichcan be optionally independently substituted with one or moresubstituents selected from: halogen, CF₃, CH₃, OCF₃, OCH₃, CN, andC(H)O; and

C¹ is thienyl, furanyl, oxazolyl or isoxazolyl, each of which can beoptionally independently substituted with one or more substituentsselected from fluorine, chlorine, CH₃, and OCF₃.

In various embodiments: A¹ is phenyl; A¹ is pyridyl; A¹ is pyrazyl; A¹is oxazolyl; A¹ is isoxazolyl; C¹ is thienyl; C¹ is furanyl; C¹ isoxazolyl; and C¹ is isoxazolyl.

Also disclosed are compounds having Formula Va or a salt thereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃and OCF₃,

with the proviso that R₁ and R₅ cannot be simultaneously hydrogen;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₇ and R₈ are independently selected from hydrogen and fluorine;

R₉ is selected from hydrogen, F, Cl, CH₃, and OCF₃; and

E is O or S.

In various embodiments of the compound of Formula Va: R₁ and R₅ areindependently selected from hydrogen and CH₃ with the proviso that R₁and R₅ cannot be simultaneously hydrogen, R₃ is fluorine, chlorine orbromine, E is S, and R₉ is hydrogen or fluorine; R₁ and R₅ areindependently selected from hydrogen and CH₃ with the proviso that R₁and R₅ cannot be simultaneously hydrogen, both R₂ and R₄ are hydrogen,R₃ is chlorine or bromine, E is O; R₁ and R₅ are independently selectedfrom hydrogen and CH₃ with the proviso that R₁ and R₅ cannot besimultaneously hydrogen, both R₂ and R₄ are hydrogen, R₃ chlorine orbromine, E is S, and R₉ is hydrogen or fluorine; R₁ and R₅ areindependently selected from hydrogen and Cl, R₃ is fluorine, chlorine orbromine, E is O, and R₉ is fluorine.

Also disclosed are compounds having Formula Vb or a salt thereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₈ is selected from hydrogen and fluorine;

R₆ and R₉ are independently selected from hydrogen, F, Cl, CH₃, andOCF₃; and

E is O or S.

In various embodiments of the compound of Formula Vb: R₁ and R₅ areindependently selected from hydrogen and CH₃ with the proviso that R₁and R₅ cannot be simultaneously hydrogen, R₃ is fluorine, chlorine andbromine, and E is O; R₁ and R₅ are independently selected from hydrogenand CH₃ with the proviso that R₁ and R₅ cannot be simultaneouslyhydrogen, R₃ is fluorine, chlorine or bromine, E is S and R₉ is hydrogenor fluorine; R₁ and R₅ are independently selected from hydrogen and CH₃with the proviso that R₁ and R₅ cannot be simultaneously hydrogen, bothR₂ and R₄ are hydrogen, R₃ is chlorine or bromine, E is O; R₁ and R₅ areindependently selected from hydrogen and CH₃ with the proviso that R₁and R₅ cannot be simultaneously hydrogen, both R₂ and R₄ are hydrogen,R₃ is chlorine or bromine, E is S, and R₉ is hydrogen or fluorine; R₁and R₅ are independently selected from hydrogen and C₁, R₃ is fluorine,chlorine or bromine, E is O, and R₉ is fluorine.

Described herein are compounds having Formula (VI) or a salt thereof

wherein,

A is an optionally substituted aryl or optionally independently singlyor multiply substituted arylalkyl or optionally independently singly ormultiply substituted heteroaryl or optionally independently singly ormultiply substituted heteroarylalkyl wherein the substituents areselected from the group consisting of halo, C₁-C₆ haloalkyl, C₆-C₁₀aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₆-C₁₀ aryl(C₁-C₆)alkyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆)alkynyl, C₁-C₆ hydroxyalkyl, amino, ureido, cyano, C₁-C₆ acylamino,hydroxy, thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy and carboxy, andC(H)O;

C is a thienyl, furanyl, oxazolyl or isoxazolyl each of which can beoptionally independently substituted with one or more with substituentsselected from: fluorine, chlorine, CH₃, and OCF₃.

In various embodiments: A is aryl; A is arylalkyl; A is heteroarylalkyl;A is heteroaryl; C is thienyl; C is furanyl; C is oxazolyl; C isisoxazolyll; A is pyridyl; A is pyrazyl; A is oxazolyl; and A isisoxazolyl; compounds in which both A and C are not thiophenyl andcompounds in which both A and C are not furanyl.

Also described herein are compounds having Formula VIa or a saltthereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₇ and R₈ are independently selected from hydrogen and fluorine;

R₉ is selected from hydrogen, F, Cl, CH₃, and OCF₃; and

E is O or S.

In various embodiments of the compound of Formula VIa: R₁ and R₅ areindependently selected from hydrogen, CH₃, F and Cl; R₁ and R₅ areindependently selected from hydrogen, CH₃, fluorine and Cl, and R₃ isCl; R₁ and R₅ are independently selected from hydrogen, CH₃, fluorineand Cl, and R₃ is Br, R₁ and R₅ are independently selected fromhydrogen, CH₃, fluorine and Cl, R₃ is Cl, and E is O; R₁ and R₅ areindependently selected from hydrogen, CH₃, fluorine and Cl, and R₃ is Brand E is O; R₁ and R₅ are independently selected from hydrogen and CH₃,and R₃ is Cl, E is O, and R₆, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen and CH₃,and R₃ is Br, E is O, and R₇, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen andfluorine, and R₃ is Cl, E is O, and R₇, R₈ and R₉ are selected fromhydrogen and fluorine; R₁ and R₅ are independently selected fromhydrogen and fluorine, R₃ is Br, E is O, and R₇, R₈ and R₉ are selectedfrom hydrogen and fluorine; R₁ and R₅ are independently selected fromhydrogen and chlorine, and R₃ is Cl, E is O, and R₇, R₈ and R₉ areselected from hydrogen and fluorine; R₁ and R₅ are independentlyselected from hydrogen and CH₃, R₃ is C₁, R₂ and R₄ are hydrogen E is O,and R₇, R₈ and R₉ are selected from hydrogen and fluorine; R₁ and R₅ areindependently selected from hydrogen and CH₃, R₂ and R₄ are hydrogen, R₃is Br, E is O, and R₇, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen andfluorine, R₂ and R₄ are hydrogen, R₃ is Cl, E is O, and R₇, R₈ and R₉are selected from hydrogen and fluorine; R₁ and R₅ are independentlyselected from hydrogen and fluorine, R₂ and R₄ are hydrogen, R₃ is Br, Eis O, and R₇, R₈ and R₉ are selected from hydrogen and fluorine; R₁ andR₅ are independently selected from hydrogen and chlorine, R₂ and R₄ arehydrogen, R₃ is Cl, E is O, and R₇, R₈ and R₉ are selected from hydrogenand fluorine.

Also described herein are compounds having Formula VIb or a saltthereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃,and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₈ is selected from hydrogen and fluorine;

R₆ and R₉ are independently selected from hydrogen, F, Cl, CH₃, andOCF₃; and

E is O or S.

In various embodiments of the compound of Formula VIb: R₁ and R₅ areindependently selected from hydrogen, CH₃, F and Cl; R₁ and R₅ areindependently selected from hydrogen, CH₃, fluorine and Cl, and R₃ isCl; R₁ and R₅ are independently selected from hydrogen, CH₃, fluorineand Cl, and R₃ is Br; R₁ and R₅ are independently selected fromhydrogen, CH₃, fluorine and Cl, R₃ is Cl, and E is O; R₁ and R₅ areindependently selected from hydrogen, CH₃, fluorine and Cl, and R₃ is Brand E is O; R₁ and R₅ are independently selected from hydrogen and CH₃,and R₃ is Cl, E is O, and R₆, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen and CH₃,and R₃ is Br, E is O, and R₇, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen andfluorine, and R₃ is Cl, E is O, and R₇, R₈ and R₉ are selected fromhydrogen and fluorine; R₁ and R₅ are independently selected fromhydrogen and fluorine, R₃ is Br, E is O, and R₇, R₈ and R₉ are selectedfrom hydrogen and fluorine; R₁ and R₅ are independently selected fromhydrogen and chlorine, and R₃ is Cl, E is O, and R₇, R₈ and R₉ areselected from hydrogen and fluorine; R₁ and R₅ are independentlyselected from hydrogen and CH₃, R₃ is C₁, R₂ and R₄ are hydrogen E is O,and R₇, R₈ and R₉ are selected from hydrogen and fluorine; R₁ and R₅ areindependently selected from hydrogen and CH₃, R₂ and R₄ are hydrogen, R₃is Br, E is O, and R₇, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen andfluorine, R₂ and R₄ are hydrogen, R₃ is Cl, E is O, and R₇, R₈ and R₉are selected from hydrogen and fluorine; R₁ and R₅ are independentlyselected from hydrogen and fluorine, R₂ and R₄ are hydrogen, R₃ is Br, Eis O, and R₇, R₈ and R₉ are selected from hydrogen and fluorine; R₁ andR₅ are independently selected from hydrogen and chlorine, R₂ and R₄ arehydrogen, R₃ is Cl, E is O, and R₇, R₈ and R₉ are selected from hydrogenand fluorine.

Described herein are compounds having Formula (VII) or a salt thereof

wherein,

A is an optionally substituted aryl or optionally independently singlyor multiply substituted arylalkyl (e.g., arylC₁₋₃alkyl or arylC₁-C₆) oroptionally independently singly or multiply substituted heteroaryl oroptionally independently singly or multiply substituted heteroarylalkyl(e.g., heteroaryl C₁₋₃alkyl or heteroaryl C₁-C₆) wherein thesubstituents are selected from the group consisting of halo, C₁-C₆haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₁-C₆)alkyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl,C₆-C₁₀ aryl(C₂-C₆) alkynyl, C₁-C₆ hydroxyalkyl, amino, ureido, cyano,C₁-C₆ acylamino, hydroxy, thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy andcarboxy, C(H)0;

C is a thienyl, furanyl, oxazolyl or isoxazolyl each of which can beoptionally independently substituted with one or more with substituentsselected from: fluorine, chlorine, CH₃, and OCF₃.

In various embodiments: A is aryl; A is arylalkyl; A is heteroarylalkyl;A is heteroaryl; C is thienyl; C is furanyl; C is oxazolyl; C isisoxazolyl; A is pyridyl; A is pyrazyl; A is oxazolyl; and A isisoxazolyl; both A and C are not thiophenyl; and both A and C are notfuranyl.

Also described herein is a compound having Formula VIIa or a saltthereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃,and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₇ and R₈ are independently selected from hydrogen and fluorine;

R₉ is selected from hydrogen, F, Cl, CH₃, and OCF₃;

E is O or S.

In various embodiments of the compound of Formula VIIa: R₁ and R₅ areindependently selected from hydrogen, CH₃, F and Cl; R₁ and R₅ areindependently selected from hydrogen, CH₃, fluorine and Cl, and R₃ isCl; R₁ and R₅ are independently selected from hydrogen, CH₃, fluorineand Cl, and R₃ is Br; R₁ and R₅ are independently selected fromhydrogen, CH₃, fluorine and Cl, R₃ is Cl, and E is O; R₁ and R₅ areindependently selected from hydrogen, CH₃, fluorine and Cl, and R₃ is Brand E is O; R₁ and R₅ are independently selected from hydrogen and CH₃,and R₃ is Cl, E is O, and R₆, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen and CH₃,and R₃ is Br, E is O, and R₇, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen andfluorine, and R₃ is Cl, E is O, and R₇, R₈ and R₉ are selected fromhydrogen and fluorine; R₁ and R₅ are independently selected fromhydrogen and fluorine, R₃ is Br, E is 0, and R₇, R₈ and R₉ are selectedfrom hydrogen and fluorine; R₁ and R₅ are independently selected fromhydrogen and chlorine, and R₃ is Cl, E is O, and R₇, R₈ and R₉ areselected from hydrogen and fluorine; R₁ and R₅ are independentlyselected from hydrogen and CH₃, R₃ is C₁, R₂ and R₄ are hydrogen E is O,and R₇, R₈ and R₉ are selected from hydrogen and fluorine; R₁ and R₅ areindependently selected from hydrogen and CH₃, R₂ and R₄ are hydrogen, R₃is Br, E is O, and R₇, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen andfluorine, R₂ and R₄ are hydrogen, R₃ is Cl, E is O, and R₇, R₈ and R₉are selected from hydrogen and fluorine; R₁ and R₅ are independentlyselected from hydrogen and fluorine, R₂ and R₄ are hydrogen, R₃ is Br, Eis O, and R₇, R₈ and R₉ are selected from hydrogen and fluorine; R₁ andR₅ are independently selected from hydrogen and chlorine, R₂ and R₄ arehydrogen, R₃ is Cl, E is O, and R₇, R₈ and R₉ are selected from hydrogenand fluorine.

Also described herein is a compound having Formula VIIb or a saltthereof,

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andC(H)O;

R₈ is selected from hydrogen and fluorine;

R₆ and R₉ are independently selected from hydrogen, F, Cl, CH₃, andOCF₃; and

E is O or S.

In various embodiments of the compound of Formula VIIa: R₁ and R₅ areindependently selected from hydrogen, CH₃, F and Cl; R₁ and R₅ areindependently selected from hydrogen, CH₃, fluorine and Cl, and R₃ isCl; R₁ and R₅ are independently selected from hydrogen, CH₃, fluorineand Cl, and R₃ is Br, R₁ and R₅ are independently selected fromhydrogen, CH₃, fluorine and Cl, R₃ is Cl, and E is O; R₁ and R₅ areindependently selected from hydrogen, CH₃, fluorine and Cl, and R₃ is Brand E is O; R₁ and R₅ are independently selected from hydrogen and CH₃,and R₃ is Cl, E is O, and R₆, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen and CH₃,and R₃ is Br, E is O, and R₇, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen andfluorine, and R₃ is Cl, E is O, and R₇, R₈ and R₉ are selected fromhydrogen and fluorine; R₁ and R₅ are independently selected fromhydrogen and fluorine, R₃ is Br, E is O, and R₇, R₈ and R₉ are selectedfrom hydrogen and fluorine; R₁ and R₅ are independently selected fromhydrogen and chlorine, and R₃ is Cl, E is O, and R₇, R₈ and R₉ areselected from hydrogen and fluorine; R₁ and R₅ are independentlyselected from hydrogen and CH₃, R₃ is Cl, R₂ and R₄ are hydrogen E is O,and R₇, R₈ and R₉ are selected from hydrogen and fluorine; R₁ and R₅ areindependently selected from hydrogen and CH₃, R₂ and R₄ are hydrogen, R₃is Br, E is O, and R₇, R₈ and R₉ are selected from hydrogen andfluorine; R₁ and R₅ are independently selected from hydrogen andfluorine, R₂ and R₄ are hydrogen, R₃ is Cl, E is O, and R₇, R₈ and R₉are selected from hydrogen and fluorine; R₁ and R₅ are independentlyselected from hydrogen and fluorine, R₂ and R₄ are hydrogen, R₃ is Br, Eis O, and R₇, R₈ and R₉ are selected from hydrogen and fluorine; R₁ andR₅ are independently selected from hydrogen and chlorine, R₂ and R₄ arehydrogen, R₃ is Cl, E is O, and R₇, R₈ and R₉ are selected from hydrogenand fluorine.

Also described herein is a method for control of unwanted nematodes, themethod comprising administering to mammals, birds, or their food,plants, seeds or soil a composition comprising an effective amount of acompound of any of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb,IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa and VIIb without theprovisos.

Also described herein is a method for control of unwanted nematodes, themethod comprising administering to mammals, birds, or their food,plants, seeds or soil a composition comprising an effective amount of acompound of any of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, Mb, IV,IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa and VIIb with the provisos.

Also described is a nematicidal composition comprising a compound of anyof Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, Vb, VI, VIa, VIb, VII, VIIa and VIIb without the provisos. at aconcentration sufficient to reduce the viability of a parasiticnematode.

Also described is a nematicidal composition comprising a compound of anyof Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, Vb, VI, VIa, VIb, VII, VIIa and VIIb with the provisos at aconcentration sufficient to reduce the viability of a parasiticnematode.

In some cases, the nematicidal composition further includes an aqueoussurfactant. Examples of surfactants that can be used include, Span 20,Span 40, Span 80, Span 85, Tween 20, Tween 40, Tween 80, Tween 85,Triton X 100, Makon 10, Igepal CO 630, Brij 35, Brij 97, Tergitol TMN 6,Dowfax 3B2, Physan and Toximul TA 15. In some cases, the nematicidalcomposition further includes a permeation enhancer (e.g., cyclodextrin).In some cases, the nematicidal composition further includes aco-solvent. Examples of co-solvents that can be used include ethyllactate, methyl soyate/ethyl lactate co-solvent blends (e.g., Steposol),isopropanol, acetone, 1,2-propanediol, n-alkylpyrrolidones (e.g., theAgsolex series), a petroleum based-oil (e.g., aromatic 200) or a mineraloil (e.g., paraffin oil)). In some cases, the nematicidal compositionfurther includes another pesticide (e.g., nematicide, insecticide orfungicide) such as an avermectin (e.g., ivermectin), milbemycin,imidacloprid, aldicarb, oxamyl, fenamiphos, fosthiazate, metam sodium,etridiazole, penta-chloro-nitrobenzene (PCNB), flutolanil, metalaxyl,mefonoxam, and fosetyl-al. Useful fungicides include, but are notlimited to, silthiofam, fludioxonil, myclobutanil, azoxystrobin,chlorothalonil, propiconazole, tebuconazole and pyraclostrobin. Thecomposition may also comprise herbicides (e.g., trifloxysulfuron,glyphosate, halosulfuron) and other chemicals for disease control (e.g.,chitosan).

Also described is a nematicidal composition comprising: oxazole,oxadiazole or thiadiazole analogs or mixtures of analogs selected fromthe group consisting of the compounds3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,3-(4-chlorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,5-(4-chloro-2-methylphenyl)-3-(furan-2-yl)-1,2,4-oxadiazole,3-(4-bromo-2-methylphenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,3-(4-fluoro-2-methylphenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(2,4-difluorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-bromo-2-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,5-(thiophen-2-yl)-3-(2,4,6-trifluorophenyl)-1,2,4-oxadiazole,3-(2,4-dichlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,3-(4-bromo-2-chlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,3-(2-chloro-4-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-chlorophenyl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(4-chlorophenyl)-5-(3-methylfuran-2-yl)-1,2,4-oxadiazole,5-(4-chloro-2-fluorophenyl)-2-(thiophen-2-yl)oxazole,2-(4-chloro-2-fluorophenyl)-5-(thiophen-2-yl)oxazole,5-(4-chloro-2-fluorophenyl)-2-(furan-2-yl)oxazole,5-(4-chloro-2-methylphenyl)-2-(furan-3-yl)oxazole,3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,5-(4-chloro-2-methylphenyl)-3-(furan-2-yl)-1,2,4-thiadiazole,3-(4-bromo-2-methylphenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,5-(furan-2-yl)-3-(4-methoxy-2-methylphenyl)-1,2,4-oxadiazole,3-(6-chloropyridin-3-yl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,3-(6-chloropyridin-3-yl)-5-(furan-2-yl)-1,2,4-thiadiazole,5-(2,4-difluorophenyl)-2-(thiophen-2-yl)oxazole,5-(2,4-difluorophenyl)-2-(furan-2-yl)oxazole,5-(4-bromo-2-fluorophenyl)-2-(thiophen-2-yl)oxazole,5-(4-bromo-2-fluorophenyl)-2-(furan-2-yl)oxazole,3-(2,4-difluorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(4-chloro-2-fluorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(4-bromo-2-fluorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(2,4-difluorophenyl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,3-(4-chloro-2-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,3-(4-bromo-2-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,5-(furan-2-yl)-3-(4-methoxy-2-methylphenyl)-1,2,4-thiadiazole,3-(2,4-dichlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(4-bromo-2-chlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(2,6-dichloropyridin-3-yl)-5-(furan-2-yl)-1,2,4-thiadiazole,5-(2,4-dichlorophenyl)-2-(thiophen-2-yl)oxazole,3-(4-chlorophenyl)-5-(thiophen-3-yl)-1,2,4-oxadiazole,5-(4-chloro-2-methylphenyl)-2-(furan-3-yl)oxazole.

In various embodiments the composition further comprises an aqueoussurfactant. Examples of surfactants that can be used include, Span 20,Span 40, Span 80, Span 85, Tween 20, Tween 40, Tween 80, Tween 85,Triton X 100, Makon 10, Igepal CO 630, Brij 35, Brij 97, Tergitol TMN 6,Dowfax 3B2, Physan and Toximul TA 15. In some cases, the nematicidalcomposition further includes a permeation enhancer (e.g., cyclodextrin).In some cases, the nematicidal composition further includes aco-solvent. Examples of co-solvents that can be used include ethyllactate, methyl soyate/ethyl lactate co-solvent blends (e.g., Steposol),isopropanol, acetone, 1,2-propanediol, n-alkylpyrrolidones (e.g., theAgsolex series), a petroleum based-oil (e.g., aromatic 200) or a mineraloil (e.g., paraffin oil)). In some cases, the nematicidal compositionfurther includes another pesticide (e.g., nematicide, insecticide orfungicide) such as an avermectin (e.g., ivermectin), milbemycin,imidacloprid, aldicarb, oxamyl, fenamiphos, fosthiazate, metam sodium,etridiazole, penta-chloro-nitrobenzene (PCNB), flutolanil, metalaxyl,mefonoxam, and fosetyl-al. Useful fungicides include, but are notlimited to, silthiofam, fludioxonil, myclobutanil, azoxystrobin,chlorothalonil, propiconazole, tebuconazole and pyraclostrobin. Thecomposition may also comprise herbicides (e.g., trifloxysulfuron,glyphosate, halosulfuron) and other chemicals for disease control (e.g.,chitosan).

Also described is a method for control of unwanted parasitic nematode(e.g., nematodes other than C. elegans), the method includingadministering to vertebrates, plants, seeds or soil a nematicidalcomposition including a compound of any of the formulae described hereinin any of the nematicidal compositions described herein.

In some instances, the nematode infects plants and the nematicidalcomposition is applied to the soil or to plants. In some instances, thenematicidal composition is applied to soil before planting. In someinstances, the nematicidal composition is applied to soil afterplanting. In some instances, the nematicidal composition is applied tosoil using a drip system. In some instances, the nematicidal compositionis applied to soil using a drench system. In some instances, thenematicidal composition is applied to plant roots or plant foliage(e.g., leaves, stems). In some instances the nematicide composition istilled into the soil or applied in furrow. In some instances, thenematicidal composition is applied to seeds. In some instances, thenematode parasite infects a vertebrate. In some instances, thenematicidal composition is administered to non-human vertebrate. In someinstances, the nematicidal composition is administered to a human. Insome instances, the nematicidal composition is formulated as a drench tobe administered to a non-human animal. In some instances, thenematicidal composition is formulated as an orally administered drug. Insome instances, the nematicidal composition is formulated as aninjectable drug. In some instances, the nematicidal composition isformulated for topical applications such as pour-ons, or for the use intags or collars.

Also described herein is a method of treating a disorder (e.g., aninfection) caused by a parasitic nematode, (e.g., M. incognita, H.glycines, B. longicaudatus, H. contortus, A. suum, B. malayi) in asubject, e.g., a host plant, animal, or person. The method includesadministering to the subject an effective amount of a compound havingFormula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va,Vb, VI, VIa, VIb, VII, VIIa or VIIb. The compound may be delivered byseveral means including pre-planting, post-planting and as a feedadditive, drench, external application, pill or by injection.

In still another aspect, methods of inhibiting a parasitic nematode(e.g., M. incognita, H. glycines, B. longicaudatus, H. contortus, A.suum, B. malayi) are provided. Such methods can include contacting thenematode (at any stage of growth), with a compound, e.g., a compoundhaving Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb,V, Va, Vb, VI, VIa, VIb, VII, VIIa or VIIb is provided.

In another aspect, methods of reducing the viability or fecundity orslowing the growth or development or inhibiting the infectivity of anematode using a nematicidal compound, e.g., a compound having FormulaI, Ia, Ib, II, IIa, IIb, III, IIIa, Mb, IV, IVa, IVb, V, Va, Vb, VI,VIa, VIb, VII, VIIa or VIIb is provided. Such methods can includecontacting the nematode with specific a compound, e.g., a compoundhaving Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, Mb, IV, IVa, IVb, V,Va, Vb, VI, VIa, VIb, VII, VIIa or VIIb; (c) reducing the viability orfecundity of the nematode parasite.

Also described is a method for reducing the viability, growth, orfecundity of a nematode parasite, the method comprising exposing thenematode to a compound having Formula I, Ia, Ib, II, IIa, IIb, III,IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa or VIIb anda method of protecting a plant from a nematode infection, the methodcomprising applying to the plant, to the soil, or to seeds of the plantan compound a compound having Formula I, Ia, Ib, II, IIa, IIb, III,IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa or VIIb.

Also described is a method for protecting a vertebrate (e.g., a bird ora mammal) from a nematode infection, the method comprising administeringto the vertebrate a compound having I, Ia, Ib, II, IIa, IIb, III, IIIa,IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa or VIIb. The birdcan be a domesticated fowl (e.g., a chicken, turkey, duck, or goose).The mammal can be a domesticated animal, e.g., a companion animal (e.g.,a cat, dog, horse or rabbit) or livestock (e.g., a cow, sheep, pig,goat, alpaca or llama) or can be a human.

Described herein are methods for controlling nematodes parasites byadministering a compound described herein. The methods includeadministering to vertebrates, plants, seeds or soil a nematicidalcomposition comprising:

an effective amount of a compound or a mixture of compounds having anyof the formulae described herein, for example one of the followingformulas:

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃,and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andCO;

R₈ is selected from hydrogen and fluorine;

R₆ and R₉ are independently selected from hydrogen, F, Cl, CH₃, andOCF₃;

B is C(H) or C(CH₃);

E is O or S.

In some cases, R₁ and R₅ are not both H.

The compositions can also include an aqueous surfactant. Examples ofsurfactants that can be used include, Span 20, Span 40, Span 80, Span85, Tween 20, Tween 40, Tween 80, Tween 85, Triton X 100, Makon 10,Igepal CO 630, Brij 35, Brij 97, Tergitol TMN 6, Dowfax 3B2, Physan andToximul TA 15. In some cases, the nematicidal composition furtherincludes a permeation enhancer (e.g., cyclodextrin). In some cases, thenematicidal composition further includes a co-solvent. Examples ofco-solvents that can be used include ethyl lactate, methyl soyate/ethyllactate co-solvent blends (e.g., Steposol), isopropanol, acetone,1,2-propanediol, n-alkylpyrrolidones (e.g., the Agsolex series), apetroleum based-oil (e.g., aromatic 200) or a mineral oil (e.g.,paraffin oil)). In some cases, the nematicidal composition furtherincludes another pesticide (e.g., nematicide, insecticide or fungicide)such as an avermectin (e.g., ivermectin), milbemycin, imidacloprid,aldicarb, oxamyl, fenamiphos, fosthiazate, metam sodium, etridiazole,penta-chloro-nitrobenzene (PCNB), flutolanil, metalaxyl, mefonoxam, andfosetyl-al. Useful fungicides include, but are not limited to,silthiofam, fludioxonil, myclobutanil, azoxystrobin, chlorothalonil,propiconazole, tebuconazole and pyraclostrobin. The composition may alsocomprise herbicides (e.g., trifloxysulfuron, glyphosate, halosulfuron)and other chemicals for disease control (e.g., chitosan).

Also featured is a method for control of unwanted nematodes comprisingadministering to vertebrates, plants, seeds or soil a nematicidalcomposition comprising an effective amount of: (a) a compound selectedfrom the group consisting of3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,3-(4-chlorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,5-(4-chloro-2-methylphenyl)-3-(furan-2-yl)-1,2,4-oxadiazole,3-(4-bromo-2-methylphenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,3-(4-fluoro-2-methylphenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(2,4-difluorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-bromo-2-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,5-(thiophen-2-yl)-3-(2,4,6-trifluorophenyl)-1,2,4-oxadiazole,3-(2,4-dichlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,3-(4-bromo-2-chlorophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,3-(2-chloro-4-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-oxadiazole,3-(4-chlorophenyl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(4-chlorophenyl)-5-(3-methylfuran-2-yl)-1,2,4-oxadiazole,5-(4-chloro-2-fluorophenyl)-2-(thiophen-2-yl)oxazole,2-(4-chloro-2-fluorophenyl)-5-(thiophen-2-yl)oxazole,5-(4-chloro-2-fluorophenyl)-2-(furan-2-yl)oxazole,5-(4-chloro-2-methylphenyl)-2-(furan-3-yl)oxazole,3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,5-(4-chloro-2-methylphenyl)-3-(furan-2-yl)-1,2,4-thiadiazole,3-(4-bromo-2-methylphenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,5-(furan-2-yl)-3-(4-methoxy-2-methylphenyl)-1,2,4-oxadiazole,3-(6-chloropyridin-3-yl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,3-(6-chloropyridin-3-yl)-5-(furan-2-yl)-1,2,4-thiadiazole,5-(2,4-difluorophenyl)-2-(thiophen-2-yl)oxazole,5-(2,4-difluorophenyl)-2-(furan-2-yl)oxazole,5-(4-bromo-2-fluorophenyl)-2-(thiophen-2-yl)oxazole,5-(4-bromo-2-fluorophenyl)-2-(furan-2-yl)oxazole,3-(2,4-difluorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(4-chloro-2-fluorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(4-bromo-2-fluorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(2,4-difluorophenyl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,3-(4-chloro-2-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,3-(4-bromo-2-fluorophenyl)-5-(thiophen-2-yl)-1,2,4-thiadiazole,5-(furan-2-yl)-3-(4-methoxy-2-methylphenyl)-1,2,4-thiadiazole,3-(2,4-dichlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(4-bromo-2-chlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole,3-(2,6-dichloropyridin-3-yl)-5-(furan-2-yl)-1,2,4-thiadiazole,5-(2,4-dichlorophenyl)-2-(thiophen-2-yl)oxazole,3-(4-chlorophenyl)-5-(thiophen-3-yl)-1,2,4-oxadiazole,5-(4-chloro-2-methylphenyl)-2-(furan-3-yl)oxazole.

Also featured is a method for control of unwanted nematodes comprisingadministering to vertebrates a nematicidal composition comprising aneffective amount of: (a) a compound selected from the group consistingof 5-(4-bromophenyl)-2-(thiophen-2-yl)oxazole,2-(2-fluorophenyl)-5-(furan-2-yl)oxazole,5-(isoxazol-5-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole,2-phenyl-5-p-tolyl-1,3,4-oxadiazole,5-(4-fluorophenyl)-2-(thiophen-2-yl)oxazole,5-(furan-2-yl)-3-p-tolyl-1,2,4-oxadiazole,2-(4-chlorophenyl)-5-(thiophen-2-yl)oxazole,2-(3-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole,5-(4-bromophenyl)-2-(furan-2-yl)oxazole,544-chlorophenyl)-2-(thiophen-3-yl)oxazole,2-(furan-2-yl)-5-phenyloxazole,5-(4-chlorophenyl)-2-(furan-2-yl)oxazole,5-(furan-2-yl)-3-(4-iodophenyl)-1,2,4-oxadiazole,5-(furan-2-yl)-3-(oxazol-2-yl)-1,2,4-oxadiazole,5-(4-propylphenyl)-3-(thiophen-2-yl)-1,2,4-oxadiazole,2-(4-bromophenyl)-5-(thiophen-2-yl)oxazole,3-(4-bromophenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,2-(3-chlorophenyl)-5-(thiophen-2-yl)oxazole.

In certain embodiments of the method the composition further comprisesan aqueous surfactant. Examples of surfactants that can be used include,Span 20, Span 40, Span 80, Span 85, Tween 20, Tween 40, Tween 80, Tween85, Triton X 100, Makon 10, Igepal CO 630, Brij 35, Brij 97, TergitolTMN 6, Dowfax 3B2, Physan and Toximul TA 15. In some cases, thenematicidal composition further includes a permeation enhancer (e.g.,cyclodextrin). In some cases, the nematicidal composition furtherincludes a co-solvent. Examples of co-solvents that can be used includeethyl lactate, methyl soyate/ethyl lactate co-solvent blends (e.g.,Steposol), isopropanol, acetone, 1,2-propanediol, n-alkylpyrrolidones(e.g., the Agsolex series), a petroleum based-oil (e.g., aromatic 200)or a mineral oil (e.g., paraffin oil)). In some cases, the nematicidalcomposition further includes another pesticide (e.g., nematicide,insecticide or fungicide) such as an avermectin (e.g., ivermectin),milbemycin, imidacloprid, aldicarb, oxamyl, fenamiphos, fosthiazate,metam sodium, etridiazole, penta-chloro-nitrobenzene (PCNB), flutolanil,metalaxyl, mefonoxam, and fosetyl-al. Useful fungicides include, but arenot limited to, silthiofam, fludioxonil, myclobutanil, azoxystrobin,chlorothalonil, propiconazole, tebuconazole and pyraclostrobin. Thecomposition may also comprise herbicides (e.g., trifloxysulfuron,glyphosate, halosulfuron) and other chemicals for disease control (e.g.,chitosan); the nematode infects plants and the nematicidal compositionis applied to the soil or to plants; the nematicidal composition isapplied to soil before planting; the nematicidal composition is appliedto soil after planting; the nematicidal composition is applied to soilusing a drip system; the nematicidal composition is applied to soilusing a drench system; the nematicidal composition is applied to plantroots; the pesticidal composition is applied to seeds; the nematicidalcomposition is applied to the foliage of plants; the nematode infects avertebrate; the nematicidal composition is administered to a bird ornon-human mammal; the nematicidal composition is administered to ahuman; the nematicidal composition is formulated as a drench to beadministered to a non-human animal; the nematicidal composition isformulated as an orally administered drug; and the nematicidalcomposition is formulated as an injectable drug.

The methods described hereon are particularly valuable for the controlnematodes attacking the roots of desired crop plants, ornamental plants,and turf grasses. The desired crop plants can be, for example, soybeans,cotton, corn, tobacco, wheat, strawberries, tomatoes, banana, sugarcane, sugar beet, potatoes, or citrus.

Also described is a nematicidal feed for a non-human vertebrateincluding:

a feed; and

a nematicidal composition, including a nematicidal composition describedherein.

In some instances, the feed is selected from the group consisting of:soy, wheat, corn, sorghum, millet, alfalfa, clover, and rye.

Also described are feeds that have been supplemented to include one ormore of the compounds described herein.

A nematicidal feed for a non-human vertebrate can comprise: (a) ananimal feed; and (b) an effective amount of a nematicidal compound ormixtures of compounds having any of the formulae described herein, forexample having one of the formula below:

wherein,

R₁ and R₅ are independently selected from hydrogen, CH₃, F, Cl, Br, CF₃,and OCF₃;

R₂ and R₄ are independently selected from hydrogen, F, Cl, Br, and CF₃;

R₃ is selected from hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, andCO;

R₈ is selected from hydrogen and fluorine;

R₆ and R₉ are independently selected from hydrogen, F, Cl, CH₃, andOCF₃;

B is C(H), or C(CH₃);

E is O or S.

In some cases, R₁ and R₅ are not both H.

The feed can be selected from the group consisting of: soy, wheat, corn,sorghum, millet, alfalfa, clover, and rye.

As used herein, an agent with “anthelmintic or anthelminthic orantihelminthic activity” is an agent, which when tested, has measurablenematode-killing activity or results in reduced fertility or sterilityin the nematodes such that fewer viable or no offspring result, orcompromises the ability of the nematode to infect or reproduce in itshost, or interferes with the growth or development of a nematode. Theagent may also display nematode repellant properties. In the assay, theagent is combined with nematodes, e.g., in a well of microtiter dish, inliquid or solid media or in the soil containing the agent. Stagednematodes are placed on the media. The time of survival, viability ofoffspring, and/or the movement of the nematodes are measured. An agentwith “anthelmintic or anthelminthic or antihelmthic activity” can, forexample, reduce the survival time of adult nematodes relative tounexposed similarly staged adults, e.g., by about 20%, 40%, 60%, 80%, ormore. In the alternative, an agent with “anthelmintic or anthelminthicor antihelminthic activity” may also cause the nematodes to ceasereplicating, regenerating, and/or producing viable progeny, e.g., byabout 20%, 40%, 60%, 80%, or more. The effect may be apparentimmediately or in successive generations.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” as employed herein by itself or as part of anothergroup refers to both straight and branched chain radicals of up to tencarbons. Typical C₁₋₁₀ alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octylgroups, which may be optionally substituted.

The term “alkenyl” as employed herein by itself or as part of anothergroup means a straight or branched chain radical of 2-10 carbon atoms,unless the chain length is limited thereto, including at least onedouble bond between two of the carbon atoms in the chain. Typicalalkenyl groups include ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

The term “alkynyl” is used herein to mean a straight or branched chainradical of 2-10 carbon atoms, unless the chain length is limitedthereto, wherein there is at least one triple bond between two of thecarbon atoms in the chain. Typical alkynyl groups include ethynyl,1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

Alkoxy groups contain oxygen substituted by one of the C1-10 alkylgroups mentioned above, which may be optionally substituted.

Alkylthio groups contain sulfur substituted by one of the C1-10 alkylgroups mentioned above, which may be optionally substituted. Alsoincluded are the sulfoxides and sulfones of such alkylthio groups.

Amino groups include —NH₂, —NHR₁₅ and —NR₁₅R₁₆, wherein R₁₅ and R₁₆ areC1-10 alkyl or cycloalkyl groups, or R₁₅ and R₁₆ are combined with the Nto form a ring structure, such as a piperidine, or R₁₅ and R₁₆ arecombined with the N and other group to form a ring, such as apiperazine. The alkyl group may be optionally substituted.

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic, bicyclic or tricyclic aromatic groups containingfrom 6 to 14 carbons in the ring.

Common aryl groups include C₆₋₁₄ aryl, preferably C6-10 aryl. TypicalC6-14 aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl,indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

Cycloalkyl groups are C3-8 cycloalkyl. Typical cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “arylalkyl” is used herein to mean any of the above-mentionedC1-10 alkyl groups substituted by any of the above-mentioned C6-14 arylgroups. Preferably the arylalkyl group is benzyl, phenethyl ornaphthylmethyl.

The term “arylalkenyl” is used herein to mean any of the above-mentionedC2-10 alkenyl groups substituted by any of the above-mentioned C6-14aryl groups.

The term “arylalkynyl” is used herein to mean any of the above-mentionedC2-10 alkynyl groups substituted by any of the above-mentioned C6-14aryl groups.

The term “aryloxy” is used herein to mean oxygen substituted by one ofthe above-mentioned C6-14 aryl groups, which may be optionallysubstituted. Common aryloxy groups include phenoxy and 4-methylphenoxy.

The term “arylalkoxy” is used herein to mean any of the above mentionedC1-10 alkoxy groups substituted by any of the above-mentioned arylgroups, which may be optionally substituted. Example arylalkoxy groupsinclude benzyloxy and phenethyloxy.

Example haloalkyl groups include C1-10 alkyl groups substituted by oneor more fluorine, chlorine, bromine or iodine atoms, e.g., fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl,chloromethyl, chlorofluoromethyl and trichloromethyl groups.

Acylamino (acylamido) groups include any C1-6 acyl (alkanoyl) attachedto an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido,butanoylamido, pentanoylamido and hexanoylamido, as well asaryl-substituted C₁₋₆ acylamino groups, e.g., benzoylamido, andpentafluorobenzoylamido.

Common acyloxy groups are any C1-6 acyl (alkanoyl) attached to an oxy(—O—) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy,pentanoyloxy and hexanoyloxy.

The term heterocycle is used herein to mean a saturated or partiallysaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ringsystem, which consists of carbon atoms and from one to four heteroatomsindependently selected from the group consisting of O, N, and S, whereinthe nitrogen and sulfur heteroatoms can be optionally oxidized, thenitrogen can be optionally quaternized, and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring, and wherein the heterocyclic ring can be substituted oncarbon or on a nitrogen atom if the resulting compound is stable.

Common saturated or partially saturated heterocyclic groups includetetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl,imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl,morpholinyl, isochromanyl, chromanyl, pyrazolidinyl pyrazolinyl,tetronoyl and tetramoyl groups.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroactoms.

Example heteroaryl groups include thienyl (thiophenyl), benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), pyranyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl,including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl(pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl,pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione,7-aminoisocoumarin, pyrido[1,2-α]pyrimidin-4-one,pyrazolo[1,5-α]pyrimidinyl, including without limitationpyrazolo[1,5-α]pyrimidin-3-yl, 1,2-benzoisoxazol-3-yl, benzimidazolyl,2-oxindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group containsa nitrogen atom in a ring, such nitrogen atom may be in the form of anN-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinylN-oxide.

The term “heteroaryloxy” is used herein to mean oxygen substituted byone of the above-mentioned heteroaryl groups, which may be optionallysubstituted. Useful heteroaryloxy groups include pyridyloxy,pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy andthiophenyloxy.

The term “heteroarylalkoxy” is used herein to mean any of theabove-mentioned C1-10 alkoxy groups substituted by any of theabove-mentioned heteroaryl groups, which may be optionally substituted.

A permeation enhancer is generally an agent that facilitates the activecompounds of the invention.

A co-solvent (i.e., a latent solvent or indirect solvent) is an agentthat becomes an effective solvent in the presence of an active solventand can improve the properties of the primary (active) solvent.

The composition can be produced in concentrated form that includeslittle or no water. The composition can be diluted with water or someother solvent prior to use to treat plants, seeds, soil or vertebrates.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1: Root galling seen in plants with no chemical applications (Falltrial).

FIG. 2: Typical root galling seen in plants treated with 2 kg/ha 4776(Fall trial).

FIG. 3: Typical root galling in plants treated with 2 kg/ha 4559 (Falltrial).

FIG. 4: Typical root galling in plants treated with 2 kg/ha of thecommercial nematicide oxamyl (Fall trial).

FIG. 5: Root galling seen in plants with no chemical applications(Summer trial).

FIG. 6: Typical root galling seen in plants treated with 4 kg/ha 5823(Summer trial).

FIG. 7: Typical root galling in plants treated with 4 kg/ha 5938 (Summertrial).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Described herein are certain compounds, some of which are oxazole,oxadiazole and thiadiazole analogs with potent broad spectrumnematicidal activity.

The nematicidal compounds may be supplied to plants exogenously, throughsprays for example. These compounds may also be applied as a seed coat.The compounds can be applied to plants or the environment of plantsneeding nematode control, or to animals or the food of animals needingnematode parasite control. The compositions may be applied by, forexample drench or drip techniques. With drip applications compounds canbe applied directly to the base of the plants or the soil immediatelyadjacent to the plants. The composition may be applied through existingdrip irrigation systems. This procedure is particularly applicable forcotton, strawberries, tomatoes, potatoes, vegetables and ornamentalplants. Alternatively, a drench application can be used where asufficient quantity of nematicidal composition is applied such that itdrains to the root area of the plants. The drench technique can be usedfor a variety of crops and turf grasses. The drench technique can alsobe used for animals. Preferably, the nematicidal compositions would beadministered orally to promote activity against internal parasiticnematodes. Nematicidal compositions may also be administered in somecases by injection of the host animal or by topical applications.

The concentration of the nematicidal composition should be sufficient tocontrol the parasite without causing significant phytotoxicity to thedesired plant or undue toxicity to the animal host. The compoundsdisclosed in this invention have a good therapeutic window.

We have surprisingly found that certain oxazole, oxadiazole andthiadiazole analogs (e.g.,5-(4-chloro-2-fluorophenyl)-2-(thiophen-2-yl)oxazole,3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-oxadiazole,3-(2,4-dichlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole) havenematicidal potencies comparable with organophosphate and carbamatestandards yet display excellent selectivity for nematodes over plantsand animals. Thus, these analogs will provide useful compounds fornematode parasite control.

The nematicidal agents described herein can be applied in conjunctionwith another pesticidal agents. The second agent may, for example, beapplied simultaneously or sequentially. Such pesticidal agents caninclude for example, avermectins for animal applications.

The aforementioned nematicidal compositions can be used to treatdiseases or infestations caused by nematodes of the followingnon-limiting, exemplary genera: Anguina, Ditylenchus, Tylenchorhynchus,Pratylenchus, Radopholus, Hirschmanniella, Nacobbus, Hoplolaimus,Scutellonema, Rotylenchus, Helicotylenchus, Rotylenchulus, Belonolaimus,Heterodera, other cyst nematodes, Meloidogyne, Criconemoides,Hemicycliophora, Paratylenchus, Tylenchulus, Aphelenchoides,Bursaphelenchus, Rhadinaphelenchus, Longidorus, Xiphinema, Trichodorus,and Paratrichodorus, Dirofiliaria, Onchocerca, Brugia,Acanthocheilonema, Aelurostrongylus, Anchlostoma, Angiostrongylus,Ascaris, Bunostomum, Capillaria, Chabertia, Cooperia, Crenosoma,Dictyocaulus, Dioctophyme, Dipetalonema, Dracunculus, Enterobius,Filaroides, Haemonchus, Lagochilascaris, Loa, Manseonella, Muellerius,Necator, Nematodirus, Oesophagostomum, Ostertagia, Parafilaria,Parascaris, Physaloptera, Protostrongylus, Setaria, Spirocerca,Stephanogilaria, Strongyloides, Strongylus, Thelazia, Toxascaris,Toxocara, Trichinella, Trichostrongylus, Trichuris, Uncinaria, andWuchereria. Particularly preferred are nematodes including Dirofilaria,Onchocerca, Brugia, Acanthocheilonema, Dipetalonema, Loa, Mansonella,Parafilaria, Setaria, Stephanofilaria, and Wucheria, Pratylenchus,Heterodera, Meloidogyne, Paratylenchus. Species that are particularlypreferred are: Ancylostoma caninum, Haemonchus contortus, Trichinellaspiralis, Trichurs muris, Dirofilaria immitis, Dirofilaria tenuis,Dirofilaria repens, Dirofilari ursi, Ascaris suum, Toxocara canis,Toxocara cati, Strongyloides ratti, Parastrongyloides trichosuri,Heterodera glycines, Globodera pallida, Meloidogyne javanica,Meloidogyne incognita, and Meloidogyne arenaria, Radopholus similis,Longidorus elongatus, Meloidogyne hapla, and Pratylenchus penetrans.

The following examples are, therefore, to be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever. All of the publications cited herein are herebyincorporated by reference in their entirety.

EXAMPLES Example 1

M. incognita testing of several nematicidal compounds in a miniaturizedgreenhouse assay.

Overview:

The test compound is dissolved in an acetone solution and added towater. A sprouted cucumber seedling is placed into a vial with dry sandand the water-chemical solution is added immediately. Twenty four hourslater Meloidogyne incognita eggs are added to the vials and 10 to 12days later the roots are evaluated for nematode galling.

Procedure:

Cucumber seeds are sprouted for 3 days in moist paper towels. Acceptablesprouts should be 3 to 4 cm long with several lateral roots justemerging. Stock solutions of chemistry are prepared in a mixture ofacetone and Triton X100 (412 mg in 500 mL) to a final concentration of 5mg/mL. The chemical stock solution is then added to 10 mL deionizedwater plus 0.015% Triton X100 and mixed thoroughly. This is enough totest each condition in triplicate. Ten mL dry sand is added to eachvial. At this time the solubility of the chemistry is visuallydetermined and recorded as either ppt (large precipitates) or cloudy(fine precipitates). Seedlings are planted by tilting the vial andlaying the seedling in the correct orientation so that the cotyledonsare just above the sand and then tilting back to cover the radicles withsand. 3.3 ml water/chemical mix is added to each vial and the vialsplaced in racks under fluorescent light banks. The vials are inoculatedtwo days after planting by adding 500 vermiform M. incognita eggs toeach vial in 50 uL of deionized or spring water. The vials are then keptunder the fluorescent lamps at ambient room temperature and watered asneeded with 1 mL deionized water, usually twice during duration of test.Harvest of the cucumber plants is done 10 to 12 days after inoculationby washing sand off the roots. A root gall rating and visualphytotoxicity rating is assigned using the following scales: Gall ratingscale (Gall: % root mass galled): 0=0-5%; 1=6-20%; 2=21-50%; and3=51-100%. The average of the triplicate gall rating is then calculated:green=0.00-0.33 (no galls); yellow=0.67-1.33 (mild galling);orange=1.67-2.33 (moderate galling); red=2.67-3.00 (severe galling).Visual phytotoxicity scale is also assigned (Vis. tox; visual reductionin root mass compared to the control): rs1=mild stunting; rs2=moderatestunting; rs3=severe stunting.

TABLE 1A Potent nematicidal oxadiazole and oxazole 2-thiophene and 2-furan analogs showing examples of substitutions compatible with highactivity 8 ppm gall Name Analog ratings 1822

0 1846

0 4417

0.33 4559

0 4775

0 4776

0 4948

0 4971

0.67 5006

0 5012

0.67 5082

1.67 5090

1.67 5132

1.33 5181

0.33 5212

1 5213

0.33 5292

0.67 5297

0.33 5456

0.67 5467

0 5468

1 5475

1.33 5478

0 5479

0 5499

0 5523

0 5527

0.67 5556

0.33 5586

0.67 5587

0 5618

1.33 5622

0 5623

0 5625

0.33 5663

0 5666

1.33 5671

0.67 5672

0 Oxamyl 0.67 (1 ppm)

A variety of single substitutions on or in the six membered aromaticring (e.g., pyridine or pyrazine in place of phenyl) of thephenyl-2-furan and phenyl-2-thiophene oxadiazoles and oxazoles arecompatible with high nematicidal activity. Examples of preferred singlesubstitutions include halogens, CH₃, CF₃, OCF₃ and OCH₃ especially inthe para position (4-position) of the phenyl ring. The phenyl ring canalso be multiply substituted in a way compatible with high nematicidalefficacy. Ring numbering system is shown below.

TABLE 1B Examples of nematicidal thiadiazole, oxadiazole and oxazoleanalogs with potency comparable to commercial standards Name Analog 1ppm gall ratings* 4776

1^(a), 1^(b), 0.33^(c), 0.33^(d) 1822

0.33^(a), 0.67^(b), 0.33^(c), 0^(d) 4559

1^(a) 5499

1^(a) 1846

1.33^(a), 0.67^(b) 5467

1.67^(a), 1.33^(b) 5479

1^(a), 0.67^(b) 5523

1^(a), 1.33^(b) 5527

1.67^(a), 1^(b) 5823

1.67^(a), 0.33^(b), 0.33^(e) 5825

0^(a), 0.33^(b) 5383

1.33^(a) 5864

1^(a) 5882

0.67^(a) 5969

1^(e) 5915

0.33^(e) 5970

1^(e) 5938

0.67^(e) 5960

0.33^(e) Oxamyl 0.67^(a), 1^(b), 1.33^(c), 1.33^(d), 1^(e) Fenamiphos0^(c), 0^(d), 0^(e) *Data with the same letters are taken from the sametest.

Several phenyl-2-furan and phenyl 2-thiophene oxadiazoles, oxazoles andthiadiazoles have nematicidal potency equivalent to the commercialcarbamate nematicide oxamyl and the commercial organophosphatenematicide fenamiphos. Oxamyl and fenamiphos are highly toxic compoundsclassified as toxicity Class I chemicals by the US EnvironmentalProtection Agency. Also noteworthy is the fact that some multiplysubstituted analogs are especially nematicidal.

TABLE 1C Nematicidal activity 3-furan and 3-thiophene analogs 1 ppm NameAnalog gall rating* 5885

1^(a) 5867

1^(a) 5869

1^(a) 5886

1.33^(b) 5887

1^(b) 1822

0^(a), 0.33^(b) 4776

1^(a), 0.33^(b), 1^(c) 5882

0.67^(c) 5876

1.67^(c) Oxamyl 1.33^(a), 1^(b), 0.67^(c) *Data with the same lettersare taken from the same test.

Strong nematicidal activity is not limited to 2-furan and 2-thiopheneanalogs and is also seen with 3-furan and 3-thiophene. Additionallycertain substitutions on the 5-membered thiophene or furan rings appearto be well tolerated.

TABLE 1D Comparison of nematicidal oxazoles and oxadiazoles withnematicidal pyrazoles and thiazoles Name Analog 8 ppm gall rating* 1 ppmgall rating* 5725

1.33^(a) 3^(a) 5735

0^(a) 2^(a) 5738

0^(a) 1.33^(a) 5741

0^(a) 1^(a) 4776

0^(a) 0^(a) 1822

0^(a) 1.33^(a) 5663

0^(b) 1.67^(b) 1787

1.67^(b) 3^(b) 5645

0^(b) 2^(b) Oxamyl 1.33^(a), 1^(b) *Data with the same letters are takenfrom the same test.

Oxazoles and oxadiazole analogs of the current invention showsignificant enhancement in nematicidal potency over comparablenematicidal pyrazoles or nematicidal thiazoles.

Example 2 General Greenhouse Testing Protocols

Soybean Planting and Growth:

Soybeans seeds are planted in 100% sand in two inch square plastic pots.Chemical treatment is done when the soybeans show the first trifoliatebeginning to emerge about 10 to 12 days after planting. At least fourhours after chemical application the nematode soybean cyst nematode(SCN) eggs are applied and 28 days after the egg inoculation the test isharvested.

Cucumber Planting and Growth

Cucumber seeds are planted in a sandy soil mixture in two inch squareplastic pots. When the cotyledons are fully opened and just as the firstleaf begins to emerge, usually 7 days after planting, chemistry for the7 day treatment is applied. One week later the chemistry for the 0 daytreatment is applied. Separate plants are used for each application. Theplants are generally in the 1-2 leaf stage now. At least four hoursafter the chemistry application the pots are inoculated with root knotnematode (RKN) eggs. Plants are rated for galling 14 days after the egginoculation.

Chemical Formulation and Application

One milligram of chemistry per four pots is equal to one kilogram perhectare of chemical. A standard test uses four replications. For ratesabove 2 kg/ha, the desired amount of chemical is weighed into a 30 mlvial (example: 8 kg/ha rate=8 mg chemical in 30 ml vial). The chemicalis dissolved in 2 ml of appropriate solvent, generally acetone. Forrates below 2 kg/ha, 2 milligrams of chemistry is weighed into the vialand dissolved in 2 ml of the solvent. The appropriate amount of chemicalconcentrate is then pipetted into a separate 30 ml vial and solvent isadded to bring the volume to 2 ml (example 0.5 kg/ha=0.5 ml ofconcentrate+1.5 ml solvent). Each dissolved concentrate is then broughtto a total of 20 milliliters using 0.05% Triton X 100 surfactantsolution.

Chemical and Nematode Application

Pots to be treated are moist but not saturated. To each of four pots,five milliliters of the appropriate chemical solution is pipetted to themedia surface making sure to avoid contact with the base of the plant.Immediately following chemical application, using a mist nozzle, the potsurface is wetted sufficiently to saturate the pot watering in thechemistry. The chemical application is done in the morning.

Nematode eggs, either SCN or RKN, are added to distilled water to createa concentration of 1000 vermiform eggs per liter of water. At least fourhours after chemical treatment the eggs are applied to the treated potsplus non-treated check plants. A small hole about 1 cm deep is punchedinto the pot surface. One milliliter of the nematode egg slurry ispipetted into the hole. Immediately afterwards the hole is gentlycovered. Watering of the test plants is then restricted to only water asneeded to prevent wilt for a period of 24 hours. After the 24 hourrestricted watering, normal sub-irrigation watering is done for theduration of the test.

TABLE 2A SCN greenhouse sand assay on soybean plants Name Analog 2 kg* 1kg* 0.5 kg* 0.25 kg* 0.1 kg* 1822

100^(a) 4559

98^(a) 4776

99^(a) — — 89^(c) — — 78^(c) 5181

100^(a) 5292

92^(a) 4417

— 94^(b) 4775

— 95^(b) 5823

— — — 69^(d) — — — 38^(d) 5915

— — — 74^(d) — — — 44^(d) 5938

— — — 89^(d) — — — 60^(d) 5939

— — — 88^(d) — — — 64^(d) Fenamiphos 98^(a) 98^(b) 94^(c) — — — 26^(d) —— — 5^(d) *Rate in kg/ha. Data shows percent control (i.e., cyst numberreduction) relative to the control blank treatment. Data with the sameletters are taken from the same test.

The oxazoles, oxadiazoles and thiadiazoles of this invention are highlyefficacious nematicides against soybean cyst nematode with potenciescomparable to fenamiphos demonstrating that this area of chemistry hasbroad nematicidal spectrum.

TABLE 2B RKN greenhouse soil assay on cucumber plants 0 day kg/ha rate*7 day kg/ha rate* Name Analog 1 0.25 0.1 0.05 1 0.25 0.1 0.05 5823

95^(a) — 98^(c) 85^(a) — 91^(c) 53^(a) — 38^(c) 5825

— 94^(b) 89^(a) 84^(b) 50^(a) 53^(a) — 97^(b) 5860

85^(a) 47^(a) 86^(a) 1822

89^(a) 81^(b) 60^(a) 64^(b) 47^(a) 7^(a) 85^(a) 75^(b) 4776

— 99^(b) 5960

— — 76^(c) — — 75^(c) — — 75^(c) 5961

— — 81^(c) — — 88^(c) — — 73^(c) Fenan — — 100^(a) 67^(a) 40^(a) 67^(a)— —  77^(b) 88^(c) 79^(c) *Data shows percent control (i.e., gallingreduction) relative to the control blank treatment. Data with the sameletters are taken from the same test.

Certain oxazoles, oxadiazoles and thiadiazoles are highly efficaciousnematicides in bioactive soil with potencies comparable to fenamiphosand activities that are resistant to biotic or abiotic degradation overa timeframe of least one week.

TABLE 2C RKN greenhouse soil assay on cucumber plants showing comparisonof two different formulations. Name Analogs Acetone 1 mg/kg* Radex 1mg/kg* 1822

94 98 5825

96 96 1846

88 86 5523

86 86 5527

91 80 5479

91 96 5467

73 88 Fenam 98 99 *Data shows percent control (i.e., galling reduction)relative to the appropriate control blank treatment. The Acetoneformulation is the standard 10% acetone in 0.05% Triton X 100formulation described above. The Radix formulation was prepared byadding 10 mg of each compound to 150 mg of a mixture of 12% Triton X100, 11% Agsolex 8, 33% Agsolex 1 and 44% Steposol SC (all by weight).Final was 6.25% active ingredient by weight.

The nematicidal activity of this area of chemistry is not compromised onmoving from a typical screening formulation with high amounts of acetoneto an emulsifiable concentrate format typical used in commercialapplications.

Example 3 Belonalaimus longicaudatus (Sting Nematode) Testing Protocols

Populations of sting (Belonolaimus longicaudatus) nematodes aremaintained on St. Augustine turf grass on soil in 15-cm pots. At testinitiation the turf is removed from the pots and the soil containingnematode eggs, juveniles, and adults is subdivided into pots eachcontaining a volume of 125 cm³. The compounds to be tested are dissolvedin 3 ml of acetone using 3, 6, or 15 mg to achieve equivalent surfacearea application rates of 2, 4, or 10 kg/ha, respectively. The 3 mlacetone stock solution is added to 30 ml of water, and 5 ml of thatsolution is used to drench each of 6 replicate test pots prepared asdescribed above. The treated pots containing nematodes are incubated inthe laboratory at ambient temperature of approximately 25° C. After 3days the soil from each pot is washed onto a modified Baermann apparatuscomprised of a screen supporting a layer of filter paper on which thesoil sample is placed and set in a dish of water. The samples are thenincubated at 25° C. for 24 hours to allow the live nematodes to migratethrough the paper and screen and into a water reservoir to be collectedfor counting with a light microscope. Nematodes that have been killed orimmobilized by the test compounds are not able to migrate into thereservoir.

TABLE 3 Efficacy against the sting nematode in a bench top soil assayName Analog 2 kg/ha 4 kg/ha 10 kg/ha Other 4417

24 13 7 4559

39 47 33 4775

15 7 4 4776

16 19 20 Positive^(#) 20 Negative^(#) 65 Water 62 *Number of nematodesrecovered from treated soil after 3 days incubation with the compound^(#)11.1 kg fenamiphos used as positive control, acetone formulationblank used to dissolve compounds in the negative control.

Certain oxazoles and oxadiazoles are highly efficacious nematicidesagainst the sting nematode which is a serious pest on turf grass. Theseanalogs have potencies comparable to fenamiphos demonstrating that thisarea of chemistry has broad nematicidal spectrum.

Example 4 C. elegans Testing Protocols

Various compounds were tested for nematicidal activity against C.elegans using contact assays in wells. The assays were performed asdescribed below. The test compounds were solubilized in DMSO at 10 mg/mlto create 100× stock solutions. A dilution series was created bydiluting the stock solution with DMSO. For each well assay 4 ul of theappropriate dilution is added to a well of a test plate.

A 400 ul aliquot of bacterial stock (in M9 buffer with ampicillin andnystatin) are added to each well of the test plate. Worms are added andthe test plate placed on a rotary shaker and held at 20° C. Worms areexamined and scored at 4 hrs, 24 hrs, 48 hrs and 72 hours.

L1 worms and L4 worms were used in the assay. L1 worms are prepared byplating eggs on a plate without a bacterial feeding layer. The eggshatch and arrest at the L1 stage. This L1 stage population is then usedto create a stock for the experiments. To create an L4 stage stock asmall number of worms are taken from an overgrown and starved plate ofworms and seeded on a plate with a bacterial feeder layer. A 25 ulaliquot of worms is added to each well in the assay.

TABLE 4 Three day C. elegans well assay of nematicidal oxadiazole andoxazole analogs L1 L1 L1 L4 L4 L4 Name Analog 1D* 2D* 3D* 1D* 2D* 3D*5820

0.4 0.4 0.4 no (25F1) (6.3F1) 5821

0.4 0.4 0.4 no (0.4F1) (0.4F1) 5822

1.6 0.4 0.4 no 1.6 (1.6F1) 5823

0.4 0.4 0.4 1.6 0.4 (0.4F1) 5824

1.6 0.4 0.4 no no (1.6F1) 5825

0.4 0.4 0.4 1.6 1.6 (1.6F1) 5826

6.3 1.6 1.6 6.3 6.3 (6.3F1) 5827

6.3 1.6 1.6 25 6.3 (6.3F1) 5828

1.6 1.6 1.6 no no no 5845

no 1.6 0.4 no 25 (25F1) 5846

1.6 0.4 0.4 1.6 1.6 (1.6F1) 5847

no 0.4 0.4 no 1.6 (1.6F1) 5848

1.6 0.4 0.4 1.6 1.6 (1.6F1) 5849

6.3 0.4 1.6 no (6.3F1) (6.3F1) 5850

1.6 0.4 0.4 1.6 1.6 (1.6F1) 5860

1.6 0.4 0.4 1.6 1.6 (1.6F1) 5861

0.4 0.4 0.4 1.6 1.6 (1.6F1) 5905

0.4 0.4 0.4 ND ND ND 5906

0.4 0.4 0.4 ND ND ND 5938

1.6 1.6 1.6 ND ND ND 5939

0.4 0.4 0.4 ND ND ND 5915

0.4 0.4 0.4 ND ND ND *EC50 in parts per million of compound after oneday, two days or three days of exposure for L1 larvae or L4 larvae. L4data in parentheses refer to effects on the second generation larvae.ND: Experiment not done.

The free living nematode C. elegans is highly diverged genetically fromthe tylenchid parasites such as soybean cyst nematode and root knotnematode. Therefore the nematicidal activity of these oxazoles,oxadiazoles and thiadiazoles against C. elegans L1 larvae and L4 larvaefurther confirms that this is chemistry is broadly active againstvarious nematode species and stages.

Example 5 Mouse Acute Toxicity Testing

Acute oral toxicity testing was performed in mice in accordance withtest method P203.UDP, as administered by Eurofins/Product SafetyLaboratories (Dayton, N.J.). CD-1/Swiss derived albino mice wereobtained and group housed in suspended solid bottom caging. The micewere fed rodent chow and filtered tap water was supplied ad libitum.Following acclimation to the laboratory setting, a group of animals wasfasted overnight by removing food from the cages. After the fastingperiod, three female mice were selected based on vitality and initialbody weights. The individual compound doses were calculated from thesebody weights.

The test substance was prepared as a 1% (50 mg/kg) or 5% (500 mg/kg)weight to weight (w/w) mixture in a 0.5% w/w solution ofcarboxymethylcellulose (CMC) in distilled water. A tissue homogenizerwas used to create a homogeneous mixture. A dose of 50 or 500 mg/kg wasadministered to three healthy mice per dose level by oral intubationusing a ball-tipped gavage needle attached to a syringe. Afteradministration, the animals were returned to their cages, and feed wasreplaced immediately after dosing.

The animals were observed for mortality, signs of gross toxicity andbehavioral changes during the first several hours post dosing and atleast once daily for up to 14 days. Body weights were recorded prior toinitiation and on Days 7 and 14 or a soon as possible after death.

Results were obtained for the following compounds:

At a dose of 50 mg/kg all animals survived, gained body weight, andappeared active and healthy. There were no signs of gross toxicity,adverse pharmacologic effects, or abnormal behavior. At a dose of 500mg/kg all animals died within three days of test substanceadministration.

At a dose of 500 mg/kg two animals appeared active and healthy andgained body weight over the 14-day observation period. One animal diedwithin four days of substance administration.

At a dose of 500 mg/kg all animals survived, gained body weight, andappeared active and healthy. There were no signs of gross toxicity,adverse pharmacologic effects, or abnormal behavior.

At a dose of 500 mg/kg two animals died within three days of substanceadministration. One animal appeared active and healthy during the entirestudy and gained weight over the 14-day observation period

At a dose of 500 mg/kg all animals survived, gained body weight, andappeared active and healthy. There were no signs of gross toxicity,adverse pharmacologic effects, or abnormal behavior.

Based on these mouse studies the oral toxicity of 1822 appears to bebetween 50 mg/kg and 500 mg/kg, that of 4776 mg/kg to be slightly lowerthan 500 mg/kg, that of 4417 to be slightly higher than 500 mg/kg andthat of 4775 and 5960 to be greater than 500 mg/kg. In comparison, theoral LD50 for aldicarb, oxamyl and fenamiphos in mice are 300 ug/kg, 2.3mg/kg and 22.7 mg/kg respectively.

Consequently, although the oxazole and oxadiazole chemistry of thisinvention has broad spectrum nematicidal activity these compoundsnonetheless show considerable improvement in safety over the commercialorganophosphate and carbamate standards and over abamectin (oral mouseLD50 13.6 mg/kg) the active ingredient the nematicidal seed treatmentAvicta™.

Example 6 Advanced Greenhouse Testing Protocols

Pre-Plant Incorporated Test (PPI)

The PPI test examines the effect of pre-incorporation of compounds insoil and longer aging to simulate in furrow methods of nematicideapplication in the field. The PPI test exposes compounds to a highervolume of soil and drying which can result in more severe soil binding.Compounds are also aged for longer periods which can lead to moreextensive biotic and abiotic degradation further limiting activity.

The chemically treated soil (sandy soil mix) for all treatment days(e.g., 7 days, 14 days, 21 days) treatments is potted into theirappropriate pots. On the same day the 7 day treatment pots are seeded.One week later eggs are applied and 14 days after egg application thetest is harvested. The 14 day treatments are planted 7 days after thefirst planting. The 14 day planting and 7 day inoculation happen on thesame day. One week later the 14 day treatments are inoculated with eggs.These are harvested 14 days after the inoculation. The 21 day treatmentsare planted 14 days after the first planting. The 14 day inoculation and21 day planting are done on the same day. One week later the 21 dayplants are inoculated with eggs. The 7 day treatment is harvested thesame day as the 21 day inoculation. Fourteen days after inoculation the21 day plants are harvested.

Treatment Planting Inoculation Harvest  7 day day 0 day 7  day 21 14 dayday 7 day 14 day 28 21 day  day 14 day 21 day 35

For each compound a stock is prepared using 4 mg material in 4 ml ofacetone. The soil is mixed by placing 80 ml of field soil and 320 ml ofsand in a plastic bag and mixing well. The formulation for treatment isdone by adding 2.13 ml (8 kg/ha rate), 1.06 ml (4 kg/ha rate) or 0.53 ml(2 kg/ha rate) to a vial and raising it with 10 ml in 0.05% X100. Soilis then treated by adding the entire 10 ml to the 400 ml of mix in thebag. The treated soil is immediately mixed well in the sealed bag todistribute the compound evenly. Approximately 95 ml is used to fill each2-inch square pot up to the top with some soil compression andflattening. For each compound and for the control treatments 4 pots arefilled. All pots are watered until moist but with no run-out through thebottom.

The PPI test simulates 8, 4 and 2 kg/ha rates incorporated 15 cm deep inthe field and is equivalent to the 2, 1 and 0.5 kg/ha drench applicationrates in the standard 2-inch pot cucumber greenhouse assay.

TABLE 6A Seven day pre-plant incorporated greenhouse studies of rootknot nematode on cucumber plants Name Analog 8 ka/ha rate* 4 kg/ha rate*1822

99 99 5213

98 85 Fenamiphos 100 96 *Data shows percent control (i.e., gallingreduction) relative to the control blank treatment.

TABLE 6B Fourteen day pre-plant incorporated greenhouse studies of rootknot nematode on cucumber plants Name Analog 8 ka/ha rate* 4 kg/ha rate*2 kg/ha rate* 1822

100^(a) 97^(a) 67^(a) 5467

100^(a) 76^(a) 71^(a) 5479

100^(a) 89^(a) 71^(a) 5523

99^(a) 87^(a) 59^(a) 5527

96^(a) 90^(a) 57^(a) 5823

100^(a) 100^(b) 98^(a) 94^(b) 85^(a) 5825

96^(a) 98^(a) 69^(a) 5915

— 99^(b) — 70^(b) 5938

— 100^(b) — 90^(b) Fenamiphos 100^(a)  99^(a) 88^(a) 100^(b) 100^(b)*Data shows percent control (i.e., galling reduction) relative to thecontrol blank treatment. Data with the same letters are taken from thesame test.

TABLE 6C Twenty one day pre-plant incorporated greenhouse studies ofroot knot nematode on cucumber plants Name Analog 8 ka/ha rate* 4 kg/harate* 1822

95 82 4776

80 50 Fenamiphos 99 84 *Data shows percent control (i.e., gallingreduction) relative to the control blank treatment.

Example 7 Fall Nematicidal Field Testing

Site Establishment

The test site was located at 3511 Highway F in New Melle, Mo., SaintCharles county. The soil was a native prairie/pasture covering siltyclay loam soil. Holes were dug using a Bobcat 763 skid loader with a12-inch auger to a depth of 18 inches. Total volume of each hole wasabout 1.2 cubic feet. Six cubic yards of topsoil and 9 tons of riversand were purchased from Dardenne Farms Topsoil. Mixing to a ratio of 4volumes sand to 1 volume soil was accomplished using a trailer-mounted 9cubic foot concrete mixer. Holes were filled and then re-filled 5 dayslater after settling. The mixture was 92.5% sand, 2.5% silt, and 5%clay. Organic matter was 0.2% and pH was 6.8.

Plots were planted with squash seeds and had a uniform stand of squashseedlings (2 per plot, 10 cm apart) with the first true leaf emergingjust prior to treatment.

Treatment and Inoculation

Treatments were arranged in a block design with the blocks laid outperpendicular to the primary slope and parallel to secondary slope.There are 7 inoculated controls and 5 non-inoculated controls and thedistributions of disease severity appeared independent of location.

Randomized complete block design ← N blk 1 blk 2 blk 3 blk 4 blk 5 blk 61 6 8 3 7 9 5 10 5 1 9 9 2 7 9 4 9 8 4 5 7 2 2 7 6 2 6 10 8 6 3 1 3 10 65 8 9 4 8 1 4 9 3 10 5 4 3 7 4 1 7 3 2 10 8 2 6 5 1

Application rates are expressed as kg of active material per hectare,and the mg per plot is based on the surface area of the bored and filledholes (0.000008559 Ha). The DC compounds were formulated immediatelybefore application as follows: 1) the amount required to treat all sixreplicates was dissolved in 300 ml of acetone, 2) for each plot 50 ml ofthat solution was added to a graduated cylinder with 2 ml of 12.5%Triton X100 and the volume was raised to 500 ml with tap water. Theresultant mix is the same as used in the standard greenhouse assays (10%acetone, 0.05% X100). The oxamyl treatments were prepared from Vydate 2Lformulated the same way. The 500 ml was placed in a watering can and theentire volume was evenly sprinkled over the surface of the plot. Norunoff occurred and pooling, if any, was short lived. The final drenchvolume was 0.58 ml/cm², compared to 0.2 ml/cm² used in our greenhouse,however the microplots are much deeper so the drench volume applied persoil volume treated is roughly the same.

TABLE 7A Compound treatment list Field A- Name Analog Rate* mount* 4417

2 17 4776

2 17 4559

2 17 Oxamyl 5 43 2 17 NT NI *Field rate in kg ai per hectare and amountof compound added in mg ai per plot. NT = non treated (i.e., inoculatedwith nematodes but not treated with chemicals) NI = non inoculated(i.e., not treated with chemicals or inoculated with nematodes)

Meloidogyne incognita eggs were harvested over a two week period andstored at approximately 5° C. until needed. A stock of 5.6 millionvermiform eggs was adjusted to 9000/ml in 620 ml. One day aftertreatment, two holes were made in each plot about 7 cm apart andequidistant from the squash plants. Five ml of egg suspension waspipetted into each hole, which was then sealed and the plot lightlywatered. A total of 90,000 vermiform eggs were added to each plot.

Early Observations

Two days after treatment slight phytotoxicity was seen with the 4417 2kg/ha treatment. The hypocotyls of affected seedlings were water-soakedat the soil line. Leaf diameter of the first true leaves measured fivedays after treatment (5 DAT) also showed a slight reduction for the 4417treatment. None of the compounds appeared to affect the onset of bloom.

TABLE 7B Root Ratings Name Analog TW28 RG28 RW28 RG43 RW43 4417

97.5 cde 25.5 abc 5.3 ab 38.2 bc 16.4 a 4776

250.8 abc 19.0 bc 7.5 ab 26.8 cd 13.0 ab 4559

150.8 cd 34.2 ab 6.4 ab 24.0 cde 13.2 ab Oxamyl5 232.1 abcd 10.5 c 6.6ab 17.3 def 12.7 b Oxamyl2 136.8 d 45.0 a 5.6 b 42.3 ab 14.3 ab NT 322.4a 38.6 a 7.9 a 54.7 a 15.5 ab NI 263.1 ab 0.4 c 6.9 ab 0.0 g 14.4 ab*Means with a letter in common are not significantly different at P =0.1 using Students T test. TW28 = top weight at 28 days after treatmentRG28 = % root galls at 28 days after treatment TW28 = root weight at 28days after treatment RG43 = % root galls at 43 days after treatment TW43= root weight at 43 days after treatment NT = non treated (i.e.,inoculated with nematodes but not treated with chemicals) NI = noninoculated (i.e., not treated with chemicals or inoculated withnematodes) Oxamyl5 and Oxamyl2 are oxamyl at 5 kg ai/ha and 2 kg ai/harespectively

The first root evaluation was at 28 DAT. The tops were cut off andweighed immediately in the field, and the roots were carefully dug outso as not to disturb the remaining plant.

The earlier phytotoxicity seen with 4417 is mirrored in a reduction intop weights at 28 DAT. However root weights 28 DAT were not affected androots weights recorded from the second harvest (43 DAT) revealed noeffect from any of the treatments.

Root gall damage was estimated at 28 DAT and 43 DAT using a percentbinning scale of 0, 1, 5, 10, 25, 33, 50, 66, 75, 90, and 100%representing the % of root mass significantly impacted by galls. At bothsampling times all three compounds provided control of root galling thatwas numerically superior to oxamyl at an equivalent rate. 4776 wasstatistically better than oxamyl at both the 28 day and the 43 day timepoint whereas 4559 was significantly better than oxamyl at the 43 daytime point.

In summary all three compounds provide equivalent or superior nematodecontrol to oxamyl under field conditions. Thus these nematicidal analogsare superior to many of the newer more selective nematicide candidateswhich lack field efficacy at reasonable use rates and are lacksufficient longevity to be of commercial interest.

Example 8 Summer Nematicidal Field Evaluation of Pre-Plant Incorporated(PPI) Compounds for Control of Meloidogyne incognita on Squash

Test plots of 33 cm diameter holes were bored 41 cm deep into clay soiland filled with a mixture of 80% sand and 20% silt loam soil. Technicalcompound for each treatment was dissolved in 50 ml acetone containing250 ul of Triton X-100 surfactant. This solution was added to 450 mlwater and poured onto 95 liters of sand/soil mixture in a rotating drummixer. While continuing to rotate the mixing drum 66 grams of chopped,galled, tomato roots was added and thoroughly distributed. The treatedsoil was sufficient to fill the top 15 cm of each of the 6 replicateplots, thus simulating a PPI treatment. The plots were then wateredlightly and a mixture of M. incognita eggs and larvae were injected 5 cmdeep at 5 points within the plot (100 k eggs/larvae in 10 ml per plot).Three-week old squash (cv. Liberator III) with 1 fully expanded trueleaf was planted 4 days after soil treatment, one per plot.

0-3 0-3 root wgt top wgt feeder root vigor vigor (g) (lbs) total fruitgall % (3 = ave) 16DAP 21DAP 31DAP 31DAP (lbs) 31DAP 31DAP 5523 4 kg 3.03.0 26.3 1.31 1.24 26 3.0 5823 4 kg 3.0 3.0 22.6 1.45 1.44 3 2.7 5891 4kg 3.0 2.8 27.5 1.43 1.22 28 3.0 5938 4 kg 2.5 2.7 24.1 1.60 1.22 9 2.75960 4 kg 3.0 3.0 32.6 1.58 1.61 24 3.3 fosthiazate 2 kg 3.0 3.0 26.42.01 1.25 5 2.3 oxamyl 4 kg 2.7 2.5 37.0 1.16 1.09 85 3.0 Blank 1.5 1.223.4 0.30 0.38 90 2.7

Chopped gall inoculum combined with eggs/juveniles provided highpressure and rapid development of symptoms. PPI applications of DC5823and DC5938 provided excellent control at 4 kg/ha. DC5523, DC5891, andDC5960 also provided significant control at 4 kg/ha.

Example 9 Seed Treatment Test of Root Knot Nematode on Cucumber Plantsand Soybean Cyst Nematode on Soybean Plants

For a given concentration the chemical is dissolved in 500 ul of acetoneand one gram of cucumber seed (RKN test) or soybean seed (SCN test) isadded (e.g., 20 mg active ingredient in 500 ul acetone plus 1 gram ofseed). The seed solutions are agitated until all seeds were thoroughlycovered with the chemical solution. The acetone is then allowed toevaporate by air drying the seeds. The seeds are planted in 2-inch potscontaining sandy soil and then the pots are inoculated with 1000Meloidogyne incognita (RKN) or 1000 Heterodera glycines (SCN) eggs perpot three days after planting. Plants are rated for galling 14 daysafter egg inoculation for RKN or 28 days after egg inoculation for SCN.

TABLE 9A Seed treatment activity against root knot nematode usingcucumber seeds 20 mg ai/gram Name Analog seed* 1822

76 4775

77 4776

58 Abamectin^(#) 84 *Data shows percent control (i.e., gallingreduction) relative to the control blank treatment. ^(#)Abamectinpositive control at 10 mg ai/gram seed.

TABLE 9B Seed treatment activity against soybean cyst nematode usingsoybean seeds Name Analog 1.5 mg* 0.375 mg* 5527

71^(a) 43^(a) 5479

88^(a) 83^(b) 67^(a) 69^(b) 1822

70^(a) 58^(a) 5847

— 80^(b) — 66^(b) 5878

— 77^(b) — 43^(b) 5953

— 77^(b) — 44^(b) Oxamyl — —   71^(b)  −4^(b) Thiodicarb −23^(a)   6^(a) Abamectin −24^(a) −14^(a) *Data shows percent cyst reductionrelative to control blank treatment. Rates are mg ai/gram seed. Datawith the same letters are taken from the same test.

Oxadiazole, thiadiazole and oxazole analogs are versatile nematicidesshowing activity as seed treatments in addition to drench applicationsand soil pre-incorporation methods.

Example 10

The Claimed Structures do not Induce an Apoptosis Marker in MammalianCells and do not Kill Nematodes by Causing Apoptosis

Previous studies have shown that induction of the pro-apoptoticcaspase-3 protease through the cleavage of specific fluorogenicsubstrates is a reliable method of measuring the induction of apoptosis,and certain chloro and bromo substituted thiophene and furan oxadiazoleswere identified after high-throughput screening for caspase-3 inductionin mammalian cells (Zhang H Z, Kasibhatla S, Kuemmerle J, Kemnitzer W,Ollis-Mason K, Qiu L, Crogan-Grundy C, Tseng B, Drewe J, Cai S X.Discovery and structure-activity relationship of3-aryl-5-aryl-1,2,4-oxadiazoles as a new series of apoptosis inducersand potential anticancer agents. J Med. Chem. 2005 48(16):5215-23).

To evaluate whether the compound classes of this invention are able toinduce apoptosis, caspase-3 activity was determined after compoundexposure in rat hepatoma derived H4IIE cells using a caspase substrate(DEVD, Asp-Glu-Val-Asp) labeled with a fluorescent molecule,7-Amino-4-methylcoumarin (AMC). Caspase 3 cleaves the tetrapeptidebetween D and AMC, thus releasing the fluorogenic green AMC. Followingthe test article exposure to cells in 96-well plates, medium wasaspirated from plates and PBS added to each well. Plates were stored at−80° C. to lyse cells and store samples until further analysis. On theday of analysis, plates were removed from freezer and thawed. Caspasebuffer with fluorescent substrate was added to each well and incubatedat room temperature for one hour. AMC release was measured in aspectrofluorometer at an excitation wavelength of 360 nm and an emissionwavelength of 460 nm. Values are expressed as relative fluorescent units(RFU). In contrast to paclitaxel, camptothecin, and staurosporine, whichwere reportedly capable of inducing apoptosis in a variety of cell linesat or below doses of 1 μM doses, no induction of caspase-3 is observedfor DC1822, DC5823, DC5915, and DC5938 at concentrations up to 300 μM inthis system.

To confirm that these compounds do not affect nematodes by induction ofapoptosis, Caenorhabditis elegans mutants defective in the apoptoticpathway, ced-3(n717) and ced-4(N1162) mutants (Ellis H M, Horvitz H R.Genetic control of programmed cell death in the nematode C. elegans.1986 Cell 44:817-829), were evaluated for susceptibility to 10 μg/mlDC5823 on NGM agar plates. No observable phenotypic difference insusceptibility between the wild-type C. elegans strain (N2 Bristol) andthe ced-3 and ced-4 mutants were observed, including time to mortality.

These data indicate that the claimed structures do not affect apoptosisin either mammalian cells or nematodes.

Example 11 Description of Synthesis of the Compounds of the Formula I toVII

The compounds of this invention of the Formulas Ito VII may be preparedusing methods known to those skilled in the art. Specifically, thecompounds of this invention with Formulae Ia and Ib can be prepared asillustrated by the exemplary reaction in Scheme 1. The alphaaminoketones 3 are prepared from the acetophenones 1 in a two-stepprocedure that involves bromination with 4(-dimethylamino)pyridinetribromide and subsequent amination of the bromide intermediate 2 withsodium diformylamide. The aminoketone 3 is then reacted with anappropriate acyl chloride 4 to yield the acylaminoketone 5. Acyclization of the linear precursor 5 to the2,5-disubstituted-1,3-oxazole analog 6 is accomplished withphosphorousoxychloride in DMF in good yields.

Specifically, the compounds of this invention with Formulae IIa and IIbcan be prepared as illustrated by the exemplary reaction in Scheme 2.The alpha aminoketone 2 is prepared from the bromide precursor 1 byamination with sodium diformylamide and then reacted with acyl chloride3 to yield the acylaminoketone 4. A cyclization of the linear precursor4 to the 2,5-disubstituted-1,3-oxazole analog 5 is accomplished withphosphorousoxychloride in DMF in good yields.

Specifically, the compounds of this invention with Formulae IIIa and IIIb can be prepared as illustrated by the exemplary reaction in Scheme 3.The benzohydrazide 1 is reacted with the acyl chloride 2 in chloroformin the presence of trietylamine (TEA) at ambient temperature to giveacyl benzohydrazide 3. A cyclization of the diacylhydrazine 3 to the2,5-disubstituted-1,3,4-oxadizaole compound 4 is accomplished withphosphorouschloride (POCl₃) in DMF.

Specifically, the compounds of this invention with Formulae IVa and IVbcan be prepared as illustrated by the exemplary reaction in Scheme 4.The benzonitrle 1 is converted to the corresponding hydroxyimidate 2when reacted with hydroxylamine hydrochloride in the presence of DIEA inmethanol at room temperature overnight. Then the benzohydroxyimidate 2is acylated with an appropriate furan or thiophene carbonyl chloride(R2-CO—Y) in the presence of pyridine, followed with DCC dehydration togive the 3,5-disubstituted-1,2,4-oxadiazole product.

Specifically, the compounds of this invention with Formulae Va and Vbcan be prepared as illustrated by the exemplary reaction in Scheme 5.

First, the appropriate analog of furan or thiophene nitrile 1 isconverted to the corresponding hydroxyimidate 2 by reacting withhydroxylamine in methanol in the presence of DIEA. Then, theintermediate 2 is reacted with the appropriately substituted benzoylchloride 3 in pyridine-dioxnae to give the desired3,5-disubstituted-1,2,4-oxadiazole product 4.

Specifically, the compounds of this invention with Formulae VIa and VIbcan be prepared as illustrated by the exemplary reaction in Scheme 6.The synthesis starts with the reaction of an appropriate benzamidesubstrate 1 with chlorocarbonylsulfenyl chloride to yield theoxathiazolone compound 2. In the next step the oxathiazolineintermediate 2 is reacted with an appropriate furan or thiophene nitrilein toluene under microwave conditions to give the desired3,5-disubstituted-1,2,4-thiadiazole product 3.

Specifically, the compounds of this invention with Formulae VIIa andVIIb can be prepared as illustrated by the exemplary reaction in Scheme7. An appropriate furan or thiophene carboxamide substrate 1 isconverted to the oxathiazolone intermediate by reacting withchlorocarbonylsulfenyl chloride. Then, the oxathiazoline intermediate 2is reacted with an appropriate benzonitrile compound in toluene undermicrowave conditions to give the desired3,5-disubstituted-1,2,4-thiadiazole product 4.

Formula Ia Example 5-(4-chloro-2-fluorophenyl)-2-(thiophen-2-yl)oxazole

A mixture of 4′-chloro-2′-fluoroacetophenone (17.5 g, 100 mmol),4-(dimethylamino)pyridine tribromide (40.0 g, 110 mmol) and acetic acid(100 mL) was stirred at room temperature for 24 h. Water (150 mL) wasadded and after stirring for 30 min the precipitated solid was collectedby filtration, washed with water, and dried in vacuo to give the desiredbromide intermediate as a white solid (24 g, 95%).

To a solution of the bromide compound (24 g, 90 mmol) in acetonitrile(300 mL) was added sodium diformylamide (9.0 g, 95 mmol). The mixturewas heated to reflux for 2 h and cooled to r.t overnight. The mixturewas filtered to remove NaBr. The filtrate was concentrated to givediformylamide intermediate as a brown oil, 23.6 g. EtOH (300 mL) and 30%HCl (90 mL) were added and the mixture was stirred at 50° C. for 5 h andcooled to room temperature overnight, during which time the productcrystallized out. The solid was collected by filtration, washed withdichloromethane, and dried to constant weight to give the desiredaminoketone hydrochloride as white solid (6.3 g, 31%). that was sued asis in the next step.

The synthesis of acylamino ketone was performed as described in theliterature (J. Med. Chem. 1986, 29, 333-341). A suspension of2-amino-1-(4-chloro-2-fluorophenyl)ethanone hydrochloride (6.3 g, 28mmol) in water (50 mL) and EtOAc (100 mL) was cooled in an ice-bath.NaHCO₃ (11.9 g, 140 mmol) was added in portions, followed by 2-thiophenecarbonyl chloride (4.25 g, 29 mmol). The mixture was stirred at roomtemperature for 16 h. Water (50 mL) was added and the mixture wasextracted with EtOAc (2×50 mL). The organic layers were combined, washedwith brine, dried (MgSO₄), filtered, and concentrated in vacuo to giveacylamino ketone 5 as yellow solid (7.7 g, 92%). The organic layers werecombined, dried (MgSO₄), and concentrated in vacuo to give crudeproduct, 7.8 g, which was purified by crystallization from EtOH (25 mL).Yield 5.0 g (69%) of yellow solid.

Molecular Formula: C₁₃H₇ClFNOS; MW 279.72

HPLC-ESMS: t_(R)=6.04 min; m/z: 279.9 (M+H); HPLC purity 98.0% (216 nm);99% (250 nm)

¹H-NMR (300 MHz, CDCl₃): 7.74-7.85 (m, 2H), 7.52-7.56 (m, 1H), 7.46-7.51(m, 1 H), 7.21-7.31 (m, 2H), 7.14-7.20 (m, 1H)

Formula IIa Example 2-(4-chloro-2-fluorophenyl)-5-(thiophen-2-yl)oxazole

A mixture of 2-(2-bromoacetyl)thiophene (2.05 g, 10 mmol), sodiumdiformyl amide (1.05 g, 11 mmol) and acetonitrile (20 mL) was heated toreflux for 4 h. The mixture was cooled to r.t. and filtered to removeNaBr. The filtrate was concentrated in vacuo to give a brown oil, 2.0 g.EtOH 930 mL) was added followed by concentrated HCl (30%, 10 mL). Themixture was stirred at r.t. overnight. Concentration in vacuo gave asticky solid, 2.1 g. The resulted aminoketone hydrochloride wascontained by some NH₄Cl (based on H1-NMR spectra) and used as is in thenext step.

A mixture of the crude amine.HCl in EtOAc (40 mL) and water (20 mL) wasvigorously stirred and cooled in ice-water bath. NaHCO₃ (8.3 g, 100mmol) was added, followed by 4-chloro-2-fluorobenzoyl chloride (1.9 g,10 mmol). The mixture was stirred at r.t. overnight. The layers wereseparated. The water layer was extracted with EtOAc (50 mL). Thecombined organic layers were washed with water, dried (MgSO₄) andconcentrated to a brown solid, 2.0 g. The resulted crude product was amixture of the desired acylaminoketone and 4-chloro-2-fluorobenzamide(formed by reaction of ammonium chloride present in the startingaminoketo compound with the acyl chloride).

The acylaminoketone intermediate was dissolved n DMF (25 mL). and thenPOCl₃ (2.3 g, 15 mmol) was added and the mixture was stirred at r.t. for2.5 days. Ice-water was added and the mixture was extracted with EtOAc(3×50 mL). The organic layer was washed with water (3×30 ml), dried(MgSO₄) and concentrated to a brown solid/oil, 1.7 g. A columnchromatography (Hep/EtOAc 2/1) gave 1.0 g of a solid which was still notpure. Crystallization from MeOH (5 mL) gave pure (0.6 g, 22%)2-(4-chloro-2-fluorophenyl)-5-(thiophen-2-yl)oxazole with HPLCpurity >99.0% (215 and 254 nm).

Molecular Formula: C₁₃H₇ClFNOS, MW 279.72; LC-MS: t_(R)=9.46 min m/z:279.9 (M+H).

¹H-NMR (300 MHz, CDCl₃): 7.98-8.08 (m, 1H), 7.22-7.42 (m, 5H), 7.08-7.14(m, 1H)

Formula IIIa Example2-(4-Chloro-phenyl)-5-thiophen-2-yl-[1,3,4]oxadiazole

To 250 mL round bottom flask was added 2.0 g (11.7 mmol, 1 eq) of4-chlorobenzhydrazide (1) in 100 mL of amelene stabilized chloroform,followed by addition of 4 mL (29.25 mmol, 2.5 eq) of TEA. Then, 1.4 mL(12.87 mmol, 1.1 eq) of 2-thiophenecarbonyl chloride (2) was addeddrop-wise and the mixture was stirred at ambient temperature for 1 h.Reaction progress was monitored by LCMS on a twelve minute gradient. Theformed white precipitate was filtered, washed with chloroform and thendried on the high vacuum for two hours. The resulting material wasconfirmed to be the desired diacylhydrazide and was used in the nextstep without further purification. The crude diacyl-hydrazide wasdissolved in 60 mL of POCl₃ under heating. The resulting mixture wasthen heated under reflux in oil bath (100-110° C.) for 5-7 h. Thereaction progress was monitored by LCMS on a twelve minute gradient.Once the cyclization reaction was completed as determined by LCMS, POCl₃was carefully evaporated in vacuum and the reaction was then neutralizedwith a 1 N solution of ammonium hydroxide. The product was extractedwith ethyl acetate (300 mL) from saturated solution of NaHCO₃ (200 mL),washed with a brine (2×200 mL), then dried over sodium sulfate, filteredand evaporated to dryness. The product was purified by flash columnchromatography (hexane→12% ethyl acetate/hexane), and thenrecrystallized from mixture of hexane/ethyl acetate (5:1) to give 1.3 gof the desired compound2-(4-Chloro-phenyl)-5-thiophen-2-yl-[1,3,4]oxadiazole (42%) as a whitesolid.

Chemical Formula: C₁₂H₇ClN₂OS; MW 262.71; ESMS: m/z 263 (M+H);

¹H-NMR (250 MHz, D₆-DMSO): 8.08-8.12 (m, 2H), 7.96-7.99 (m, 2H),7.69-7.72 (m, 2H), 7.32-7.35 (m, 1H)

Formula IVa Example3-(4-Chloro-2-methyl-phenyl)-5-furan-2-yl-[1,2,4-]oxadiazole

In a 500 mL round-bottom flask, 4-chloro-2-methylbenzonitrile (10 g, 66mmol) was dissolved in 200 mL of methanol. To the mixture was addedhydroxylammonium chloride (4.56 g, 66 mmol) followed by DIEA(diisopropylethylamine) (23 mL, 132 mmol). The mixture was heated atreflux for overnight. The solvents were removed. The residue wasdissolved in 200 mL of CHCl₃. To the mixture was added 2-furoyl chloride(10.5 ml, 66 mmol) followed by DIEA (23 mL, 132 mmol). After reactioncompletion, the mixture was extracted with chloroform and water. Theorganic layer was separated, washed with brine, dried over Na₂SO₄,filtered and evaporated to dryness. The residue was dissolved in 200 mLof dioxanes. To the mixture was added 1 eq of DIC(N,N′-diisopropylcarbodiimide) followed by 1 eq of DIEA. The mixture wasthen heated at reflux overnight. After reaction completion, the mixturewas cooled down. The solvents were removed in vacuo. The residue wasthen extracted with ethyl acetate and water. The organic layer wasseparated, washed with brine, dried over Na₂SO₄, filtered and evaporatedto dryness. The crude was purified by flash chromatography on silica gelin a 0-20% ethyl acetate/hexanes gradient to afford 4.96 g of thedesired compound3-(4-Chloro-2-methyl-phenyl)-5-furan-2-yl-[1,2,4]oxadiazole as a whitepowder in an overall yield of 28.8%.

Molecular Formula: C₁₃H₉ClN₂O₂; MW 260.04; HPLC purity 99.9% (254 nm);LC-ESMS: t_(R)=7.55 min; m/z 261.1 (M+1);

¹H-NMR (250 MHz, D₆-DMSO): 8.18-8.19 (m, 1H), 7.98-8.01 (d, J=8.3, 1H),7.64-7.65 (m, 1H), 7.52-7.56 (m, 1H), 7.46-7.50 (m, 1H), 6.87-6.89 (m,1H), 2.59 (s, 3H)

Formula IVa Example3-(4-Bromo-2-methyl-phenyl)-5-furan-2-yl-1,2,4′-oxadiazole

In a 500 mL round-bottom flask, 4-bromo-2-methylbenzonitrile (5 g, 25mmol) was dissolved in 200 mL of methanol. To the mixture was addedhydroxylammonium chloride (1.72 g, 25 mmol) followed by DIEA(diisopropylethylamine) (8.7 mL, 50 mmol). The mixture was heated atreflux for overnight. The solvents were removed. The residue wasdissolved in 200 mL of CHCl₃. To the mixture was added 2-furoyl chloride(3.97 ml, 25 mmol) followed by DIEA (8.7 mL, 50 mmol). After reactioncompletion, the mixture was extracted with chloroform and water. Theorganic layer was separated, washed with brine, dried over Na₂SO₄,filtered and evaporated to dryness. The residue was dissolved in 200 mLof dioxanes. To the mixture was added 1 eq of DIC(N,N′-diisopropylcarbodiimide) followed by 1 eq of DIEA. The mixture wasthen heated at reflux overnight. After reaction completion, the mixturewas cooled down. The solvents were removed in vacuo. The residue wasthen extracted with ethyl acetate and water. The organic layer wasseparated, washed with brine, dried over Na₂SO₄, filtered and evaporatedto dryness. The crude was purified by flash chromatography on silica gelin a 0-20% ethyl acetate/hexanes gradient to afford 2.23 g of thedesired compound3-(4-Bromo-2-methyl-phenyl)-5-furan-2-yl-[1,2,4]-oxadiazole as a whitepowder in an overall yield of 36%.

Chemical Formula: C₁₃H₉BrN₂O₂; MW: 305.13; HPLC Purity >99.0%; (254 nm)ESMS: t_(R)=7.81 min; m/z 305.1 (M+1);

¹H-NMR (250 MHz, D₆-DMSO): 8.18-8.19 (m, 1 H), 7.92 (d, J=8.3, 1H),7.58-7.70 (m, 3H), 6.86-6.90 (m, 1H), 2.59 (s, 3H)

Formula Va Example5-(4-chloro-2-methylphenyl)-3-(furan-2-yl)-1,2,4-oxadiazole

To a solution of 2-furonitrile (1.9 g, 20 mmol) in MeOH (50 mL) wasadded hydroxylamine hydrochloride (1.4 g, 20 mmol) and triethylamine(2.1 g, 20 mmol). The mixture was heated to reflux overnight. Aftercooling to room temperature the mixture was concentrated in vacuo. Theresidue was stirred with EtOAc (50 mL). The solid was filtered off andthe filtrate was concentrated to a thick oil, 2.5 g (99%). The H-NMRspectra was in accordance with the desired hydroxyamidine compound whichwas contaminated with Et₃N.HCl. The crude product resulted in thisreaction was used without the purification in the next step.

To a suspension of 4-chloro-2-methylbenzoic acid (3.4 g, 20 mmol) indichloromethane (50 mL) was added one drop of DMF followed byoxalylchloride (3.2 g, 25 mmol). The mixture was stirred overnightduring which time all solid dissolved. The mixture was concentrated invacuo and stripped with dichloromethane to remove excess oxalylchloride.The residual acid chloride was taken in dioxane/pyridine (10/1, 55 mL)and hydroxyamidine compound (2.5 g, 20 mmol) was added. The mixture washeated to reflux for 3 h. After cooling to room temperature, water wasadded (100 mL) and the resulting solid was collected by filtration anddried to give 6.2 g of crude product. Recrystallizaton from MeOH (40 mL)gave pure 5-(4-chloro-2-methylphenyl)-3-(furan-2-yl)-1,2,4-oxadiazole2.6 g (yield 47%).

Molecular Formula: C₁₃H₉ClN₂O₂; MW 260.04; HPLC purity: >99.9% (216 nm);99.9% (324 nm); LC-ESMS: t_(R)=9.46 min; m/z 261.1 (M+1);

¹H-NMR (300 MHz, CDCl₃): 8.10 (dd, J=8.1, 1H), 7.63-7.66 (m, 1H),7.32-7.42 (m, 2H), 7.18-7.22 (d d, J=2.7, 0.9, 1H), 6.58-6.62 (m, 1H),2.89 (s, 3H)

Formula VIa Example(2,4-dichlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole

A mixture of 2,4-dichlorobenzamide (25 g, 131.5 mmol) andchlorocarbonylsulfenylchloride (19 g, 145 mmol) in toluene (150 mL) washeated to reflux for 4 h (HCl-gas formation was observed with pH paper).After cooling to r.t. the mixture was concentrated in vacuo to give thedesired oxathiazolone compound as an off-white solid (32.4 g, 99%). thatwas used in the next without purification. In a 20 mL vial a mixture ofoxathiazolone 8a (2 g, 8 mmol) and 2-furonitrile (10 g, 107 mmol) washeated in the microwave at 190° C. for 20 min. The reaction wasperformed 10 times and the combined mixture was distilled (Kugerrohr) at100° C./20 mbar to remove excess 2-furonitrile (the recovered2-furonitrile was used again). The mixture was further distilled at 150°C./10 mbar to remove the byproduct nitrile 10 (yellow solid, 6.5 g,47%). The residue of the distillation (circa 10 g) was taken indichloromethane (50 mL), filtered and the filtrate concentrated to abrown solid, 8 g. Recrystallization by dissolution in hot MeOH (50 mL)and addition of water (10 mL) gave pure(2,4-dichlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole as brown solid,4.7 g, in a 20% yield.

Chemical Formula: C₁₂H₆Cl₂N₂OS; MW: 297.16; HPLC-ESMS: t_(R)=6.5; m/z:296.96; 298.95 (M+1); HPLC purity >99% (221 nm), >99% (263 nm), >99.0%(306 nm)

¹H-NMR (300 MHz, CDCl₃): 7.90 (dd, J=8.4, 1H), 7.57-7.58 (m, 1H), 7.29(dd, J=8.4, 1.8) 7,48, d, J=1.8, 1H), 7.15-7.20 (m, 1H), 6.55-6.59 (m,1H)

Formula VIa Example3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-thiadiazole

A magnetically stirred mixture of acid 4-chloro-2-methylbenzoic acid (50g, 0.29 mol), dichloromethane (200 mL), and 0.5 mL DMF was cooled in anice-bath. The cooler was connected to a gas absorption trap. Oxalylchloride (44.5 g, 0.35 mmol) was added dropwise in 1 h. The mixture wasstirred at r.t. overnight during which time all solid dissolved. Thesolution was concentrated in vacuo and stripped with dichloromethane toremove excess oxalyl chloride. The residue was taken in THF (200 mL) andmechanically stirred in an ice-water bath. Aqueous 25% ammonia (100 mL)was added in 15 min, which resulted in the formation of a precipitate.The THF was removed with the rotavap and extra water (100 mL) was added.The suspension was stirred at r.t. overnight. The solid was collected byfiltration and dried in vacuo to give 2-methyl-4-chlorobenzamide (43.7g, yield 89%) that was used without purification in the next step.

A mechanically stirred mixture of 2-methyl-4-chlorobenzamide (31.35 g,185 mmol), toluene (400 mL), and chlorocarbonylsulfenylchloride (25 g,190 mmol) was heated to reflux for 3 h. After cooling to roomtemperature the mixture was concentrated in vacuo to give a yellow solid40 g (95%). H-NMR showed that this was a mixture of the desiredoxathiazolone compound and nitrie by-product and starting amide in aratio 85:10:5. This mixture was used in the next step without furtherpurification.

The crude oxathiazolone compound (2.0 g, 8.8 mmol) and 2-furonitrile (16g, 170 mmol) were mixed and heated for 20 min at 190° C. in themicrowave. Ten batches were combined and Kugelrohr distilled at 100°C./30 mbar to recover excess 2-furonitrile (used again in next microwavereactions). The residue was further distilled at 150° C./20 mbar toremove the nitrile by-product. The residue, 5.5 g was combined with theresidue of another ten microwave reactions (4.5 g) and purified bycolumn chromatography. The resulting 4.5 g (85% pure by HPLC) wasrecrystallized from MeOH (50 mL) to give pure3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-thiadiazole as lightbrown solid, 3.6 g (7.5% yield).

Chemical Formula: C₁₃H₉ClN₂OS; MW: 278.7; HPLC-ESMS: t_(R)=6.36 min andm/z 277.0 (M+1); HPLC purity: >95% (220 nm) 95% (270 nm).

¹H-NMR (300 MHz, CDCl₃): 8.06, (dd, J=7.8, 1H), 7.62-7.63 (m, 1H),7.22-7.31 (m, 3H), 6.61-6.63 (m, 1H), 2.66 (s, 3H)

Formula VIa Example 3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole

A mechanically stirred mixture of 4-chlorobenzamide (20.23 g, 130 mmol),toluene (150 mL), and chlorocarbonylsulfenylchloride (19 g, 145 mmol)was heated to reflux for 3 h. After cooling to r.t. the mixture wasconcentrated in vacuo to give a yellow solid foam, 27.65 g (100%). H-NMRshowed that this was almost pure oxathiazolone compound that was used asis in the next step. The oxathiazolone compound (1.71 g, 8 mmol) and2-furonitrile (15 g, 160 mmol) were mixed and heated for 20 min at 190°C. in the microwave. Ten batches were combined and Kugelrohr distilledat 100° C./30 mbar to recover excess 2-furonitrile (used again in nextmicrowave reactions). The residue was further distilled at 150° C./20mbar to remove the nitrile byproduct. The residue, 5 g, wasrecrystallized from MeOH to give 3.5 g of solid. This was combined withthe residue of another 5 microwave reactions (2.6 g) and purified bycolumn chromatography. The resulting 4.4 g (90% pure by HPLC) wasrecrystallized from Heptane/EtOAc=7/1 (50 mL) to give pure3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole as light brownsolid, 3.35 g (10% yield).

Chemical Formula: C₁₂H₇ClN₂OS; Molecular Weight: 262.71; HPLC— ESMS:

t_(R)=6.06 min; m/z: 263.00, 264.99 (M+1)

¹H-NMR (300 MHz, CDCl₃): 8.24-8.33 (m, 2H), 7.63-7.65 (m, 1H), 7.42-7.50(m, 2H), 7.23-7.28 (m, 1H), 6.62-64 (m, 1H)

Formula VIIa Example5-(2-chloro-4-methylphenyl)-3-(furan-2-yl)-1,2,4-thiadiazole

A magnetically stirred mixture of 2-furoylamide (prepared from2-furoylchloride and aqueous ammonia, 1.13 g, 10 mmol) andchlorocarbonylsulfenylchloride (2.0 g, 15 mol) in toluene (20 mL) washeated to reflux for 4 h. After cooling to room temperature the mixturewas concentrated to give 1.7 g of the desired oxathiazolone as a yellowsolid (almost in a quantitative yield) that was used in the next stepwithout further purification.

A mixture of the oxathiazolone compound (170 mg, 1 mmol) and4-chloro-2-methylbenzonitrile (3.03 g, 20 mmol) was heated in themicrowave at 190° C. for 20 min. A second reaction was performed and themixtures were combined. Excess of the nitrile by-product (furonitrile)were removed in vacuo (120° C., 0.3 mbar). The residual brown solid (100mg) was taken in hot MeOH (10 mL) and decanted from insolable material(presumably sulphur). The MeOH solution was left at room temperatureovernight. The precipitated solid was collected and dried to givecompound 5-(2-chloro-4-methylphenyl)-3-(furan-2-yl)-1,2,4-thiadiazole asbrown solid, 40 mg (7%). NMR conform structure.

Chemical Formula: C₁₃H₉ClN₂OS; MW: 278.7; HPLC-ESMS: t_(R)=6.36 min andm/z 277.01 (M+1); HPLC purity: 93.5 (216 nm) 91% (324 nm); ¹H-NMR (300MHz, CDCl₃): 7.87 (dd, J=8.1, 1H), 7.51-7.60 (m, 1H), 7.24-7.32 (m, 2H),7.15-7.20 (m, 1H), 6.50-6.56 (m, 1H), 2.58 (s, 3H)

What is claimed is:
 1. A compound of Formula (VI), Formula (VII), or a salt thereof,

wherein A is an optionally substituted aryl or optionally substituted arylalkyl or optionally substituted heteroarylalkyl, wherein said substituents are selected from the group consisting of halo, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₁-C₆)alkyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆) alkynyl, C₁-C₆ hydroxyalkyl, amino, ureido, cyano, C₁-C₆ acylamino, hydroxy, thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy and carboxy, and C(H)O; and C is thienyl, furanyl, oxazolyl or isoxazolyl, each of which can be optionally independently substituted with one or more with substituents selected from the group consisting of fluorine, chlorine, CH₃, and OCF₃.
 2. The compound of claim 1 wherein A is an optionally substituted aryl.
 3. The compound of claim 1 wherein A is an optionally substituted arylalkyl.
 4. The compound of claim 1 wherein A is an optionally substituted heteroarylalkyl.
 5. The compound of claim 1 wherein C is optionally substituted thienyl.
 6. The compound of claim 1 wherein C is optionally substituted furanyl.
 7. The compound of claim 1 wherein C is optionally substituted oxazolyl.
 8. The compound of claim 1 wherein C is optionally substituted isoxazolyl.
 9. The compound of claim 1 wherein A is phenyl.
 10. The compound of claim 1 wherein the compound is of Formula VIa or a salt thereof,

wherein R₁ and R₅ are independently selected from the group consisting of hydrogen, CH₃, F, Cl, Br, CF₃ and OCF₃; R₂ and R₄ are independently selected from the group consisting of hydrogen, F, Cl, Br, and CF_(3;) R₃ is selected from the group consisting of hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, and C(H)O; R₇ and R₈ are independently selected from the group consisting of hydrogen and fluorine; R₉ is selected from the group consisting of hydrogen, F, Cl, CH₃, and OCF₃; and E is O or S.
 11. The compound of claim 10 wherein E is O.
 12. The compound of claim 10 wherein E is S.
 13. The compound of claim 1 wherein the compound is of Formula VIb or a salt thereof,

wherein R₁ and R₅ are independently selected from the group consisting of hydrogen, CH₃, F, Cl , Br, CF₃, and OCF₃; R₂ and R₄ are independently selected from the group consisting of hydrogen, F, Cl, Br, and CF₃; R₃ is selected from the group consisting of hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, and C(H)O; R₈ is selected from the group consisting of hydrogen and fluorine; R₆ and R₉ are independently selected from the group consisting of hydrogen, F, Cl, CH₃, and OCF₃; and E is O or S.
 14. The compound of claim 13 wherein E is O.
 15. The compound of claim 13 wherein E is S.
 16. The compound of claim 1 wherein the compound is of Formula VIIa or a salt thereof,

wherein R₁ and R₅ are independently selected from the group consisting of hydrogen, CH₃, F, Cl, Br, CF₃, and OCF₃; R₂ and R₄ are independently selected from the group consisting of hydrogen, F, Cl, Br, and CF₃; R₃ is selected from the group consisting of hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, and C(H)O; R₇ and R₈ are independently selected from the group consisting of hydrogen and fluorine; R₉ is selected from hydrogen, F, Cl, CH₃, and OCF₃; and E is O or S.
 17. The compound of claim 16 wherein E is O.
 18. The compound of claim 16 wherein E is S.
 19. The compound of claim 1 wherein the compound is of Formula VIIb or a salt thereof,

wherein R₁ and R₅ are independently selected from the group consisting of hydrogen, CH₃, F, Cl, Br, CF₃ and OCF₃; R₂ and R₄ are independently selected from the group consisting of hydrogen, F, Cl, Br, and CF₃; R₃ is selected from the group consisting of hydrogen, CH₃, CF₃, F, Cl, Br, OCF₃, OCH₃, CN, and C(H)O; R₈ is selected from the group consisting of hydrogen and fluorine; R₆ and R₉ are independently selected from the group consisting of hydrogen, F, Cl, CH₃, and OCF₃; and E is O or S.
 20. The compound of claim 19 wherein E is O.
 21. The compound of claim 19 wherein E is S.
 22. A method for control of plant parasitic nematodes, the method comprising administering to a plant, a seed or soil a composition comprising an effective amount of a compound of claim 1 or a salt thereof.
 23. The method of claim 22 wherein the composition comprises a surfactant.
 24. The method claim 22 wherein the composition includes one or more of an insecticide, a fungicide, a herbicide, or other pesticide.
 25. The method of claim 22 wherein the composition comprises a co-solvent.
 26. The method of claim 24 wherein the insecticide, fungicide, herbicide or the pesticide is selected from the group consisting of avermectin, ivermectin, milbemycin, imidacloprid, aldicarb, oxamyl, fenamiphos, fosthiazate, metam sodium, etridiazole, penta-chloro-nitrobenzene (PCNB), flutolanil, metalaxyl, mefenoxam, fosetyl-al, silthiofam, fludioxonil, myclobutanil, azoxystrobin, chlorothalonil, propiconazole, tebuconazole, pyraclostrobin, trifloxysulfuron, glyphosate and halosulfuron.
 27. The method of claim 22 wherein the plant parasitic nematode is selected from Pratylenchus spp, Heterodera spp, Globodera spp, Meloidogyne spp, Rotylenchulus spp, Hoplolaimus spp, Belonolaimus spp, Longidorus spp, Paratrichodorus spp, Ditylenchus spp, Xiphinema spp, Helicotylenchus spp, Radopholus spp, Hirschmanniella spp, Tylenchorhynchus spp, and Trichodorus spp.
 28. The method of claim 22 wherein the composition is applied to seeds.
 29. A seed produced in accordance with the method of claim
 28. 30. A seed having a coating comprising a compound of claim 1 or a salt thereof.
 31. A seed having a coating comprising a compound selected from the group consisting of: 3-(4 -chloro-2-methylphenyl)-5-(furan-2-yl)-1,2,4-thiadiazole; 3-(2,4-dichlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole; 3-(4-bromo-2-methylphenyl)-5-(furan-2-yl)-1,2,4-thiadiazole; 3-(4-bromo-2-chlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole; 3-(4-chlorophenyl)-5-(thien-2-yl)-1,2,4-thiadiazole; 3-(4-chlorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole; 3-(4-chloro-2-fluorophenyl)-5-(furan-2-yl)-1,2,4-thiadiazole; and 5-(2-chloro-4-methylphenyl)-3-(furan-2-yl)-1,2,4-thiadiazole.
 32. A method for control of plant parasitic nematodes, the method comprising administering to a plant, a seed or soil a composition comprising an effective amount of a compound of claim 31 or a salt thereof.
 33. A seed having a coating comprising a compound of claim 31 or a salt thereof. 